1h-pyrrolo[2,3-b] pyridine derivatives and their use as kinase inhibitors

ABSTRACT

The inventions relates to compounds of (I) and therapeutic uses thereof: (I) The terms Z, Y, and R 1  are as defined in the claims.

FIELD OF INVENTION

This invention relates to novel 1H-pyrrolo[2,3-b]pyridine derivativeshaving checkpoint kinase 1 (CHK1) inhibitory activity, to the use ofsuch compounds in medicine, in relation to the treatment of cancer, viathe inhibition of aberrant cell proliferation, and to pharmaceuticalcompositions containing such compounds.

BACKGROUND OF THE INVENTION

DNA damaging cytotoxic chemotherapeutic agents and ionizing radiationare the mainstay of current cancer treatment regimens. These therapiesare effective, especially when administered in combinations, against awide variety of neoplasms and are likely to remain the standard of carefor cancer treatment for the foreseeable future. These agents, due totheir mechanism of action, have limitations which restrict their overalleffectiveness. As these agents target DNA, they are effective againstany cell especially those actively replicating and therefore lack tumorcell specificity. Administration is usually at the maximum tolerateddose (MTD) resulting in a narrow therapeutic index and toxicity tonormal tissue especially those with an actively dividing cell componentsuch as the gastrointestinal tract, hematological system and otherorgans. Acquired or intrinsic resistance can further limit theusefulness of these agents making many patients' tumors refractory tothe drug. Multiple mechanisms can contribute to acquired resistanceincluding reduced cellular levels of active drug (through increasedmetabolism, detoxification or active efflux), increased DNA repair, lossof p53 or attenuation of apoptotic signaling.

Despite inducing DNA damaging through multiple mechanisms (e.g.topoisomerase inhibition, direct DNA alkylation or reduction ofdeoxyribonucleotides), DNA damaging cytotoxic chemotherapeutic agentssuch as cisplatin, irinotecan or gemcitabine activate cell cyclecheckpoints. Cell cycle checkpoints exist to protect the fidelity of DNAreplication and division, and ensure the correct timing of cell cycleevents. As DNA cannot be replaced, these pathways are critical inprotecting genomic integrity and preventing the onset of cancer.Checkpoints exist at multiple phases of the cell cycle and can beactivated during the G1-, S- or G2-phase of the cell cycle in responseto DNA damage. Alternatively, the mitotic checkpoint is activated byimproper chromosome attachment to a bipolar spindle and exists to ensureaccurate chromosome segregation and protect against aneuploidy. Inmammalian cells, the key effector proteins are p53 and the checkpointkinases Chk1 and Chk2. A large proportion of human cancers are defectivefor the p53-pathway in some form thereby lacking a functional G1checkpoint. Therefore, these human tumors are highly reliant on the Chkkinases to protect them in response to DNA damaging insults.

DNA damaging agents, along with ionizing radiation, activate DNA damagecheckpoints and induce cell cycle arrest in G1, S, or at the G2-Mtransition. Damage sensors, such as the Mre11 complex (Mre11, Rad50 andNbs1) that recognize double strand breaks, or the Rad17 and theRad9-Hus1-Rad1 complex that recognize replication stress, activate thecentral transducing kinases ATM and ATR. In turn, these kinases directlyactivate the effector kinases Chk1 and Chk2. Chk1 and Chk2 negativelyregulate the Cdc25 family of phosphatases thereby preventing cell cycleprogression as well as directly modulating repair proteins resulting inincreased lesion repair. This allows the cell to pause replication,repair the damaged DNA, then resume replication. Biochemical and geneticstudies have demonstrated Chk1 to be essential and indispensable for theS- and G2-M checkpoints.

Chk1 inhibition, therefore, represents a novel therapeutic strategy toincrease the lethality of DNA-damaging chemotherapeutic drugs in p53pathway defective cancers. Abrogation of the remaining intact checkpointshould result in increased tumor cell death. Chk1 inhibitors havedemonstrated potentatiation of a range of cytotoxic chemotherapy drugsboth in vitro and in a range of pre-clinical models of human cancerincluding gemcitabine, irinotecan and paclitaxel. This “syntheticlethality” approach should increase the therapeutic activity of thechemotherapeutic drug without increasing the systemic toxicity as normalcells should remain protected by their functional p53 pathway. Chk1inhibitors have, therefore, the potential to be combined with a widerange of cytotoxic chemotherapeutic agents for the treatment of adiverse selection of human cancers. This approach has started to betested clinically with several small molecule inhibitors of Chk1(GDC0425, GDC0575, LY2603618 and LY2606368) currently undergoing PhaseI/II clinical evaluation in combination with gemcitabine, irinotecan andcytarabine. Additional agents including AZD7762, PF00477736, SCH900776and XL844 have undergone Phase I trials but the development of theseagents has subsequently been stopped.

WO2009140320 and WO2009089352 disclose pyrrolopyridines as CHK1 and/orCHK2 inhibitors.

It has now been found that certain 1H-pyrrolo[2,3-b]pyridine derivativesshow efficacy as CHK1 inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to a class of substituted1H-pyrrolo[2,3-b]pyridine compounds useful as CHK1 inhibitors, forexample, for the treatment of cancer. A core 1H-pyrrolo[2,3-b]pyridinetemplate, with optional substitution in the 4 and 5 position and in thethree position by a substituted-pyrazolyl amido-linked group areprinciple characterising features of the compounds with which theinvention is concerned.

The present invention is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:each Z is independently (Alk)_(n)-R_(n)-(Alk)_(n)-X,wherein each Alk is independently (C₁ to C₁₂) alkylene or (C₂ to C₁₂)alkenylene, each of which may be optionally substituted;each n is independently 0 or 1;each R is independently optionally substituted arylene or heteroarylene,or optionally substituted cycloalkylene or heterocyclic, —O—, —S—,—(C═O)—, —(C═S)—, —SO₂—, —C(═O)O—, —C(═O)NR^(A)—, —C(═S)NR^(A)—,—SO₂NR^(A)—, —NR^(A)C(═O)—, —NR^(A)SO₂— or NR^(A)— wherein R^(A) ishydrogen, C₁-C₆ alkyl, —C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(C₁-C₆alkoxy) or C₁-C₆ alkoxy;each X is independently halogen, —H, —OR^(A), NR^(A)R^(A), optionallysubstituted aryl or heteroaryl, or optionally substituted cycloalkyl orheterocyclic, CN or C(halogen)_(a)H_(b), where a is 1, 2, or 3, and b is(3-a);Y is optionally substituted aryl or heteroaryl, or optionallysubstituted cycloalkyl or heterocyclic; andR¹ is H or C₁-C₆ alkyl.

DESCRIPTION OF PREFERRED EMBODIMENTS Terminology

As used herein, the term “(C_(a)-C_(b))alkyl” wherein a and b areintegers refers to a straight or branched chain alkyl radical havingfrom a to b carbon atoms. Thus when a is 1 and b is 6, for example, theterm includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term “(C_(a)-C_(b))alkylene” wherein a and b areintegers refers to a saturated hydrocarbon chain having from a to bcarbon atoms and two unsatisfied valences, such as —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂— and —CH₂C(CH₃)₂CH₂—. For the avoidance ofdoubt, it is to be understood that a divalent branched chain(C_(a)-C_(b))alkylene radical includes those wherein one of the carbonsof the hydrocarbon chain is a ring carbon of a cycloalkyl ring (ie is aspiro centre).

As used herein the term “cycloalkyl” refers to a saturated carbocyclicradical having from 3-8 carbon atoms and includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

As used herein the term “carbocyclic” refers to a mono- or bi-cyclicradical whose ring atoms are all carbon, and includes monocyclic aryl,cycloalkyl, and cycloalkenyl radicals, provided that no single ringpresent has more than 8 ring members. A “carbocyclic” group includes amono-bridged or multiply-bridged cyclic alkyl group.

As used herein the term “aryl” refers to a mono-, bi- or tri-cycliccarbocyclic aromatic radical. Illustrative of such radicals are phenyl,biphenyl and napthyl.

As used herein the term “heteroaryl” refers to a mono-, bi- ortri-cyclic aromatic radical containing one or more heteroatoms selectedfrom S, N and O. Illustrative of such radicals are thienyl, benzthienyl,furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl,benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl,benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl,benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.

As used herein the unqualified term “heterocyclyl” or “heterocyclic”includes “heteroaryl” as defined above, and in particular refers to amono-, bi- or tri-cyclic non-aromatic radical containing one or moreheteroatoms selected from S, N and O, to groups consisting of amonocyclic non-aromatic radical containing one or more such heteroatomswhich is covalently linked to another such radical or to a monocycliccarbocyclic radical, and to a mono-, bi- or tri-cyclic non-aromaticradical containing one or more heteroatoms selected from S, N and Owhich is mono-bridged or multiply-bridged. Illustrative of such radicalsare pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl,pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl,benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl,ethylenedioxyphenyl, maleimido and succinimido groups. Unless otherwisespecified in the context in which it occurs, the term “substituted” asapplied to any moiety herein means substituted with at least onesubstituent, for example selected from (C1-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, mercapto(C₁-C₆)alkyl,(C₁-C₆)alkylthio, halo (including fluoro and chloro), trifluoromethyl,trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COOR^(A),—COR_(A), —SO₂R^(A), —CONH₂, —SO₂NH₂, —CONHR^(A), —SO₂NHR^(A),—CONR^(A)R^(B), —SO₂NR^(A)R^(B), —NH₂, —NHR^(A), —NR^(A)R^(B), —OCONH₂,—OCONHR^(A), —OCONR^(A)R^(B), —NHCOR^(A), —NH^(B)COOR^(A),—NR^(B)COOR^(A), —NHSO₂OR^(A), —NR^(B)SO₂OR^(A), —NHCONH₂, —NR^(A)CONH₂,—NHCONHR^(B), —NR^(A)CONHR^(B), —NHCONR^(A)R^(B) or —NR^(A)CONR^(A)R^(B)wherein R^(A) and R^(B) are independently a (C₁C₆)alkyl group, or R^(A)and R^(B) when attached to the same nitrogen may form a cyclic aminoring such as a morpholinyl, piperidinyl or piperazinyl ring. An“optional substituent” or “substituent” may be one of the foregoingsubstituent groups.

As used herein the term “salt” includes base addition, acid addition andquaternary salts. Compounds of the invention which are acidic can formsalts, including pharmaceutically or veterinarily acceptable salts, withbases such as alkali metal hydroxides, e.g. sodium and potassiumhydroxides, alkaline earth metal hydroxides e.g. calcium, barium andmagnesium hydroxides, with organic bases e.g. N-ethyl piperidine,dibenzylamine and the like. Those compounds (I) which are basic can formsalts, including pharmaceutically or veterinarily acceptable salts withinorganic acids, e.g. with hydrohalic acids such as hydrochloric orhydrobromic acids, sulphuric acid, nitric acid or phosphoric acid andthe like, and with organic acids e.g. with acetic, tartaric, succinic,fumaric, maleic, malic, salicylic, citric, methanesulphonic andp-toluene sulphonic acids and the like.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Compounds of the invention are expected to be isolatable as hydrates andsolvates. The term ‘solvate’ is used herein to describe a molecularcomplex comprising the compound of the invention and a stoichiometricamount of one or more pharmaceutically acceptable solvent molecules, forexample, ethanol. The term ‘hydrate’ is employed when said solvent isH₂O. Any reference herein to a compound of formula (I) is to beunderstood as including such hydrates and solvates.

Compounds with which the invention is concerned which may exist in oneor more stereoisomeric form, because of the presence of asymmetric atomsor rotational restrictions, can exist as a number of stereoisomers withR or S stereochemistry at each chiral centre or as atropisomeres with Ror S stereochemistry at each chiral axis. The invention includes allsuch enantiomers and diastereoisomers and mixtures thereof.

So-called ‘pro-drugs’ of the compounds of formula (I) are also withinthe scope of the invention. Thus certain derivatives of compounds offormula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body, be convertedinto compounds of formula (I) having the desired activity, for example,by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.Further information on the use of prodrugs may be found in Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Also included within the scope of the invention are metabolites ofcompounds of formula (I), that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites include

-   -   (i) where the compound of formula (I) contains a methyl group,        an hydroxymethyl derivative thereof (—CH₃—>—CH₂OH):    -   (ii) where the compound of formula (I) contains an alkoxy group,        an hydroxy derivative thereof (—OR—>—OH),    -   (iii) where the compound of formula (I) contains a tertiary        amino group, a secondary amino derivative thereof (—NR¹R²->—NHR¹        or —NHR²),    -   (iv) where the compound of formula (I) contains a secondary        amino group, a primary derivative thereof (—NHR¹—>—NH²),    -   (v) where the compound of formula (I) contains a phenyl moiety,        a phenol derivative thereof (-Ph->-PhOH), and    -   (vi) where the compound of formula (I) contains an amide group,        a carboxylic acid derivative thereof (—CONH₂>COOH).

PREFERRED EMBODIMENTS

Variable substituents present in compounds (I) will now be furtherdescribed. It is to be understood in the further description that anydisclosed substituent or substituent class may be present in anycombination with any of the other disclosed substituent classes.Specific examples of the variable substituents include those present inthe compounds of the Examples herein.

Preferably, the group “alk” is (C₁ to C₆) alkylene or (C₂ to C₆)alkenylene.

Preferably, at least one of the “Z” groups is located on either the 4-or 5-position of the pyridine ring. More preferably, at least one Zgroup is located on the 5-position of the ring. Most preferably, the Zgroups are located on the 4- and 5-positions of the ring.

Preferably, X and/or Z is a solubilising group. Many such solubilisinggroups are known in medicinal chemistry. Examples of solubilising groupsare morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, ethylamino,isopropylamino, diethylamino, cyclohexylamino, cyclopentylamino,methoxyethylamino, piperidin-4-yl, N-acetylpiperazinyl,methylsulfonylamino, thiomorpholinyl, thiomorpholinyldioxide,4-hydroxyethylpiperidinyl, and 4-hydroxypiperidinyl.

In a preferred embodiment Y is phenyl or heteroaryl optionallysubstituted with C₁ to C₆ alkyl, OR^(A), halogen or C₁ to C₆ alkoxy.More preferably Y is pyridyl, pyrrolyl, phenyl, or phenyl substitutedwith methyl, O-methyl, bromine or chlorine.

In a yet further preferred embodiment, Y is optionally substituted aryl.

Preferably, Y is optionally substituted phenyl. More preferably, Y isunsubstituted phenyl.

Preferably, a compound of the invention is according to one of thespecific examples, or a pharmaceutically acceptable salt thereof.

R¹ is preferably H or Me. More preferably, R¹ is H.

R^(A) is preferably is H or C₁-C₆ alkyl. In an embodiment R^(A) is—C₁-C₆ alkyl(cycloalkyl) such as CH₂-cyclopropyl, CH₂-cyclopentyl orCH₂-cyclohexyl.

In an embodiment at least one Z is H, halogen, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutednitrogen-containing heterocycle, C₁ to C₆ alkyl or OR^(A). In aparticularly preferred embodiment the optional substituent on thenitrogen-containing heterocycle is NR^(A)R^(A).

In a preferred embodiment one Z group is H, halogen, OR^(A) or C₁ to C₆alkyl, and the other Z group is optionally substituted aryl oroptionally substituted nitrogen-containing heterocycle. In aparticularly preferred embodiment the optional substituent on thenitrogen-containing heterocycle is NR^(A)R^(A).

In a preferred embodiment Z is (Alk)_(n)-optionally substitutedarylene-(Alk)_(n)-optionally substituted heterocycle.

In an alternative preferred embodiment Z is optionally substitutedheteroaryl or optionally substituted nitrogen-containing heterocycle.

In a preferred embodiment, the compounds of the invention are accordingto formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:Z₁ and Z₂ are independently (Alk)_(n)-R_(n)-(Alk)_(n)-X, andAlk, n, R, X, Y, R^(A) and R¹ are as defined in claim 1.

Preferably in the compound of formula (Ia) Z₁ is halogen, phenyl, OR^(A)or C₁ to C₆ alkyl, and Z₂ is optionally substituted aryl or optionallysubstituted heterocycle.

Preferably in the compound of formula (Ia) Z₂ is halogen, CF₃,cyclopropyl, phenyl, OR^(A) or C₁ to C₆ alkyl, and Z₁ is optionallysubstituted aryl or optionally substituted heterocycle.

Preferably the terms “heterocycle” or “nitrogen-containing heterocycle”when used in the context of compounds of formula (I) or (Ia) representan optionally substituted piperidine, piperazine or morpholine ring.

In an embodiment Z₁ is R—X, and Z₂ is X.

In an alternative embodiment Z₂ is R—X, and Z₁ is X.

In a further embodiment Z₁ is R-Alk-X, and Z₂ is X.

In a yet further embodiment Z₂ is R-Alk-X, and Z₁ is X.

Utility

The present invention may be employed in respect of a human or animalsubject, more preferably a mammal, more preferably a human subject.

As used herein, the term “treatment” as used herein includesprophylactic treatment.

Compounds of the invention may be used alone in the treatment of cancersand autoimmune disorders such as organ transplant rejection, lupus,multiple sclerosis, rheumatoid arthritis and osteoarthritis. Inhibitorsof CHK1 have demonstrated utility in improving the efficacy of currentDNA-damage inducing radiotherapy or chemotherapeutic regimens for cancertreatment. The compound of formula (I) can be used in combination forthe treatment of cancer with radiation therapy or one or more cytotoxicor cytostatic drugs, or drugs which induce cytotoxicity or cytostasis.The compound of the invention and the other component (may be in thesame pharmaceutical formulation or in separate formulations foradministration simultaneously or sequentially.

Non-limiting examples of chemotherapeutic agents, radiotherapeuticagents and other active and ancillary agents are set forth below.

(i) Alkylating agents.

(ii) Nitrogen mustards such as

  Chlorambucil Cyclophosphamide Ifosfamide Mechlorethamine Melphalan

(iii) Nitrosoureas such as

  carmustine (BCNU) Iomustine (CCNU) semustine (methyl-CCNU)

(iv) Ethylenimine/Methyl-melamine such as

  hexamethylmelamine (HMM/altetamine) thriethylenemelamine (TEM)trethylene thiophosphoramide (thiotepa)

(v) Alkyl sulphonates such as busulphan.

(vi) Triazines such as dacarbazine (DTIC).

(vii) Antimetabolites such as the Folic acid analogues such as

  Methoxtrexate pemetrexed (multi-targeted antifolate) Trimetrexate

(viii) Pyrimidine analogues such as

  2,2′-difluorodeoxy-cytidine 5-azacytidine 5-fluorouracil cytosinearabinoside (araC/cytarabine) Fluorodeoxyuridine Gemcitabine

(ix) Purine analogues such as

  2-chlorodeoxyadenosine (cladribine/2-CdA) 2′-deoxycoformycin(pentostatin) 6-Mercaptopurine 6-thioguanine Azathioprineerthyrohydroxynonyl-adenine (EHNA) fludarabine phosphate

(x) Type I Topoisomerase Inhibitors such as

  Camptothecin Irinotecan Topotecan

(xi) Biological response modifiers such as G-CSF and GM-CSF.

(xii) Differentiation agents such as retinoic acid derivatives.

(xiii) Hormones and antagonists.

(xiv) Adrenocorticosteroids/antagonists such as

  Ainoglutethimide Dexamethasone prednisone and equivalents

(xv) Progestins such as

  hydroxyprogesterone caproate medroxyprogesterone acetate megestrolacetate

(xvi) Estrogens such as

  Diethylstilbestrol ethynyl estradiol/equivalents

(xvii) Antiestrogens such as tamoxifen.

(xviii) Androgens such as

  testosterone propionate fluoxymesterone/equivalents

(xix) Anti-androgens such as

  Flutimide gonadotropin-releasing hormone analogues Leuprolide

(xx) Nonsteroidal antiandrogens.

(xxi) Natural products.

(xxii) Antimitotic drugs.

(xxiii) Taxanes such as

  docetaxel (Taxotere) estramustine/estramustine phosphate Paclitaxelvinblastine (VLB) vinca alkaloids Vincristine Vinorelbine

(xxiv) Epipodophylotoxins such as etoposide or teniposide.

(xxv) Antibiotics such as

  actimomycin D aphidicolin Bleomycin Dactinomycin daunomycin(rubidomycin) doxorubicin (adriamycin) mitomycin CMitroxantroneidarubicin splicamycin (mithramycin)

(xxvi) Enzymes such as L-asparaginase and L-arginase.

(xxvii) Radiosensitizers such as

  5-bromodeozyuridine 5-idoddeoxyuridine BromodeoxycytidineDesmethylmisonidazole EO9 Etanidazole Metronidazole MisonidazoleNicotinamide Nimorazole Pimonidazole RB 6145 RSU 1069 SR4233

(xxviii) Platinum coordination complexes such as

  Anthracenedione Carboplatin Cisplatin Mitoxantrone oxaliplatin

(xxix) Substituted ureas such as hydroxyurea.

(xxx) Methyhydrazine derivatives such as N-methylhyrazine (MIH) andprocarbazine.

(xxxi) Adrenocortical suppressant mitocane (o,p′-DDD) ainoglutethimide.

(xxxii) Cytokines such as interferon (α, β, γ) and interleukin-2.

(xxxiii) Photosensitisers such as

  bacteriochlorophyll-a benzoporphyrin derivatives hematoporphyrinderivatives napthalocyanines Npe6 pheboride-a photofrin phthalocyaninestin etioporphyrin (SnET2) zinc phthalocyanines

(xxxiv) Radiation such as

  gamma radiation infrared radiation microwave radiation ultravioletlight visible light X-ray

(xxxv) Molecular targeted therapeutics

  mTOR inhibitors PI3 Kinase inhibitors MEK inhibitors Wee1 inhibitors

CHK1 inhibitors have recently shown preclinical activity as singleagents in a diverse range of human cancers including but not limited toovarian cancer, triple negative breast cancer, neuroblastoma, melanoma,pancreatic cancer, hematological cancers and cancers with defects in DNArepair pathways such as Fanconi's Anaemia.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the causative mechanism and severity ofthe particular disease undergoing therapy. In general, a suitable dosefor orally administrable formulations will usually be in the range of0.1 to 3000 mg, once, twice or three times per day, or the equivalentdaily amount administered by infusion or other routes. However, optimumdose levels and frequency of dosing will be determined by clinicaltrials as is conventional in the art.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. The orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone, fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine, tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica, disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with H₂O or other suitablevehicle before use. Such liquid preparations may contain conventionaladditives such as suspending agents, for example sorbitol, syrup, methylcellulose, glucose syrup, gelatin hydrogenated edible fats, emulsifyingagents, for example lecithin, sorbitan monooleate, or acacia,non-aqueous vehicles (which may include edible oils), for example almondoil, fractionated coconut oil, oily esters such as glycerine, propyleneglycol, or ethyl alcohol, preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and if desired conventional flavouringor colouring agents.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

There are multiple synthetic strategies for the synthesis of thecompounds (I) with which the present invention is concerned, but allrely on known chemistry, known to the synthetic organic chemist. Thus,compounds according to formula (I) can be synthesised according toprocedures described in the standard literature and are well-known tothe one skilled in the art. Typical literature sources are “Advancedorganic chemistry”, 4^(th) Edition (Wiley), J March, “ComprehensiveOrganic Transformation”, 2^(nd) Edition (Wiley), R. C. Larock, “Handbookof Heterocyclic Chemistry”, 2^(nd) Edition (Pergamon), A. R. Katritzky),review articles such as found in “Synthesis”, “Acc. Chem. Res.”, “Chem.Rev”, or primary literature sources identified by standard literaturesearches online or from secondary sources such as “Chemical Abstracts”or “Beilstein”. Such literature methods include those of the preparativeExamples herein, and methods analogous thereto.

Examples of methods known in the art of organic chemistry in general, bywhich the compounds of the present invention may be prepared, areincluded in the following reaction schemes and procedures.

EXAMPLES

The following examples illustrate the preparation of specific compoundsof the invention and are not intended to be limiting of the full scopeof the invention. Persons skilled in the art should recognize that thechemical syntheses described here may be adapted to prepare othercompounds of the invention. Indeed, alternative methods for preparingcompounds of this invention are deemed to be within the scope of thisinvention.

Example 1 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to the route outlined inScheme 1.

Step 1: Preparation of 5-Bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine

5-Bromo-1H-pyrrolo[2,3-b]pyridine (470 mg, 2.39 mmol) was added inportions to a stirring solution of fuming nitric acid (2.5 mL) at 0° C.After addition the reaction was stirred at 0° C. for 30 minutes and thencarefully added to a mixture of ice/H₂O (25 mL) and stirred for 30minutes. The solids were separated via filtration and the filter cakewashed with copious amounts of H₂O and then iso-hexane prior to dryingin vacuo to afford the desired title compound, 484 mg, 84%.

Step 2: Preparation of 5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylamine

5-Bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine was stirred in glacial aceticacid (6 mL) at 85° C. and to this, was added a solution oftin(II)chloride dihydrate (936 mg, 4.15 mmol) in conc. HCl (1 mL), dropwise. After addition the reaction was heated at 85° C. for a further 2hours and then allowed to cool to room temperature. The reaction mixturewas poured onto a mixture of rapidly stirring ice/H₂O (30 mL) and the pHwas adjusted to 9 by the careful addition of a 50% aqueous solution ofsodium hydroxide. This aqueous mixture was extracted with DCM (3×25 mL)and the combined extracts were washed with H₂O, saturated aqueous sodiumchloride, dried (MgSO₄) and concentrated in vacuo to yield the desiredcompound, 115 mg, 66%.

Step 3: Preparation of Title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid (5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylamine (60 mg, 0.28 mmol),1-benzyl-1H-pyrazole-4-carboxylic acid (62 mg, 0.31 mmol) andtriethylamine (57 mg, 80 uL, 0.56 mmol) were stirred in dimethylformamide (1 mL).O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HATU) (106 mg, 0.28 mmol) was added and the reaction was stirred atroom temperature for 4 hours. The reaction mixture was partitionedbetween EtOAc and saturated sodium hydrogen sulphate solution and theorganics separated and washed with saturated aqueous sodium chloride(×4), dried (MgSO₄) and solvent removed in vacuo to afford a brownsolid. The residue was purified by flash chromatography on SiO₂ elutingfirst with 50% EtOAc/DCM and then 5% MeOH/DCM. The fractions containingpure product were combined and concentrated in vacuo to afford the titlecompound as a tan solid, 35 mg, 31%.

LC/MS: RT=2.22 Min (270 nm), m/z=396 [M+H], 394 [M−H]. Total run time3.75 min (short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ5.41 (s, 2H), 7.28-7.41 (m, 5H), 7.84 (d, 1H), 8.08(s, 1H), 8.28 (d, 1H), 8.45 (s, 1H), 8.48 (d, 1H), 9.88 (s, 1H), 11.69(br s, 1H)

Example 2 1-Benzyl-1H-pyrazole-4-carboxylic acid(1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to the route outlined inScheme 1, and using the methodology described for Example 1, Steps 1, 2and 3, substituting 1H-pyrrolo[2,3-b]pyridine (150 mg, 1.27 mmol) for5-bromo-1H-pyrrolo[2,3-b]pyridine in Step 1. The title compound wasisolated as a cream solid, 60.3 mg, 35.8%.

LC/MS: RT=1.95 Min (270 nm), m/z=318 [M+H], 316 [M−H]. Total run time3.75 min (short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 7.06 (dd, 1H), 7.28-7.41 (m, 5H), 7.74(d, 1H), 8.08 (s, 1H), 8.18 (dd, 1H), 8.22 (dd, 1H), 8.44 (s, 1H), 9.87(s, 1H), 11.41 (br d, 1H)

Example 3 1-Benzyl-1H-pyrazole-4-carboxylic acid(4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared by a similar route to that shown inScheme 1.

Step 1: Preparation of 4-Bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine

c.HNO₃ (0.93 mL) was added drop wise to a solution of a H₂SO₄ (0.64 mL)at 0° C. 4-Bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) in c.H₂SO₄(9 mL) was added slowly, keeping the temperature at 0° C. After additionthe reaction was stirred for a further hour at 0° C. before pouringcarefully onto rapidly stirring ice/H₂O (100 mL). The suspension wasstirred for 30 mins and then the solids separated via filtration. Thefilter cake was washed with copious amounts of H₂O before drying invacuo at 40° C., to afford the desired compound, 1.9 g, 77.3%

Step 2: Preparation of 4-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylamine

4-Bromo-3-nitro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.07 mmol) was heatedin 48% aqueous hydrobromic acid (4 mL) at 70° C. and then tin (II)chloride dihydrate (2.26 g, 10 mmol) was added in portions. Afteraddition the reaction was heated at 70° C. for a further 1 hour and thencooled before carefully adding to stirring ice/H₂O (15 mL). Thissolution was basified to pH12 using sodium hydroxide solution, and theinsoluble material separated via filtration. The filtrate was extractedwith DCM (3×100 mL) and the combined extracts were washed with H₂O andsaturated aqueous sodium chloride, dried (MgSO₄) and concentrated invacuo. This afforded the desired compound, 230 mg, 52.5%, which was usedwithout further purification.

Step 3: Preparation of Title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid (4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound (cream solid, 145 mg, 66.5%) was prepared asdescribed in Example 1, Step 3, substituting4-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylamine (117 mg, 0.55 mmol) for5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylamine.

LC/MS: RT=2.12 Min (270 nm), m/z=396 [M+H], 394 [M−H]. Total run time3.75 min (short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.39 (s, 2H), 7.28-7.41 (m, 6H), 7.61 (d, 1H), 8.03(s, 1H), 8.07 (d, 1H), 8.39 (s, 1H), 9.43 (s, 1H), 11.99 (br s, 1H)

Example 4 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared from Example 1.1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (50 mg, 0.13 mmol),phenylboronic acid (16.9 mg, 0.14 mmol), K₂CO₃ (53.9 mg, 0.39 mmol) andPd(dppf)Cl₂ (9.5 mg, 0.01 mmol) were combined in THF/H₂O (1.1 mL: 0.12mL) and thoroughly degassed. The reaction mixture was heated at 120° C.for 1 hour under microwave irradiation and then it was diluted withEtOAc. The organic layer was separated and the aqueous extracted withanother portion of EtOAc. The combined organics were washed with H₂O,saturated aqueous sodium chloride, dried (MgSO₄) and solvent removed invacuo to afford a brown gum. This crude material was purified byautomated column chromatography, eluting with DCM to 5% MeOH/DCM.Fractions found to contain pure material were combined and solventremoved in vacuo to afford the desired product as a pale brown solid, 27mg, 54%.

LC/MS: RT=1.23 Min (270 nm), m/z=394 [M+H]. Total run time 1.9 min(super short pos), HP1200

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 7.28-7.41 (m, 6H), 7.5 (m, 2H), 7.71(dd, 2H), 7.83 (d, 1H), 8.10 (s, 1H), 8.47 (s, 1H), 8.51 (d, 1H), 8.54(d, 1H), 9.92 (s, 1H), 11.51 (br d, 1H).

Example 5 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-piperidin-1-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared from Example 1.1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (75 mg, 0.19 mmol),piperidine (0.03 mL, 0.28 mmol),2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (8.83 mg, 0.02 mmol),chloro-(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butylether adduct (15.5 mg, 0.02 mmol) were added to a 0.5-2.0 mL microwavevial. The vial was sealed, evacuated and backfilled with nitrogen.Lithium bis(trimethylsilyl)amide solution, 1.0M in THF, (0.45 mL, 0.45mmol) was added and reaction mixture was heated at 65° C. for 18 hours.The reaction was allowed to cool and the mixture was quenched with 1NHCl, diluted with DCM, washed with H₂O, dried (phase separator) andsolvent removed in vacuo to afford a brown solid. This crude materialwas purified by automated column chromatography, eluting with DCM 10%MeOH/DCM (gradient). Fractions found to contain product were combinedand solvent removed in vacuo to afford a brown solid, 11 mg, 14%.

LC/MS: RT=1.02 Min (270 nm), m/z=401 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.49-1.51 (m, 2H), 1.65-1.73 (m, 4H), 3.01-3.07 (m,4H), 5.41 (s, 2H), 7.28-7.41 (m, 5H), 7.69 (s, 1H), 7.76 (s, 1H), 8.05(d, 1H), 8.07 (s, 1H), 8.44 (s, 1H), 9.75 (s, 1H), 11.11 (br d, 1H)

Example 6N-{4-[(3R)-3-aminopiperidin-1-yl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl}-1-benzyl-1H-pyrazole-4-carboxamide

The title compound was prepared according to the route outlined inScheme 2.

Step 1: Preparation of4-bromo-1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridine

Sodium hydride, 60% dispersion in mineral oil (0.49 g, 12.18 mmol) wasadded in portions to 4-bromo-1H-pyrrolopyridine (2 g, 10.15 mmol) in THF(45 mL) at 0° C. and stirred for 15 minutes. Triisopropylsilyl chloride(2.31 g, 2.57 mL, 12 mmol) was then added to the reaction mixture dropwise at 0° C. After addition the cooling was removed and the reactionmixture allowed to attain RT, where it was stirred for a further 1 hour.The suspension was then cooled to about 0-5° C. and quenched withsaturated aqueous ammonium chloride (30 mL). The aqueous phase wasextracted with EtOAc (3×30 mL) and the combined organic phases werewashed with saturated aqueous sodium chloride, dried (MgSO₄) and solventremoved in vacuo to afford a yellow oil. The crude material was purifiedby flash chromatography, eluting with iso-hexane. Fractions found tocontain pure product were combined and solvent removed in vacuo toafford the desired compound as an oil, 3.5 g, 97.6%.

Step 2: Preparation of4-fluoro-1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridine

n-Butyllithium solution, 2.5M in hexanes (2.52 mL, 11.3 mmol) was addeddrop wise to a solution of4-bromo-1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridine (2.0 g,5.66 mmol) in Et₂O (60 mL) at −78° C. under a nitrogen atmosphere, andthe mixture stirred for 30 minutes at −78° C. and for 45 mins at −5° C.to give a pale yellow solution. The resulting solution was cooled to−78° C., and a solution of N-fluorobis(phenylsulphonyl)amine (2.05 g,6.51 mmol) in THF (10 mL) was added drop wise. The mixture stirred for afurther 3 hours at −78° C., and then quenched by the addition ofsaturated aqueous ammonium chloride solution. The organic layer wasseparated and the aqueous layer was extracted with Et₂O (2×50 mL) andthe combined extracts washed with saturated aqueous sodium chloridesolution. The solution was dried over anhydrous MgSO₄ and concentratedto a yellow gum. The crude material was purified by flashchromatography, eluting with iso-hexane. Fractions found to contain pureproduct were combined and solvent removed in vacuo to afford the desiredcompound as a colourless oil, 1.3 g, 78.5%.

Step 3: Preparation of5-Bromo-4-fluoro-1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridine

4-fluoro-1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridine (833.0 mg,2.85 mmol) in THF (34 mL) at −78° C. was treated drop wise withsec-butyllithium solution, 1.4M in cyclohexane (4.48 mL, 6.27 mmol). Thereaction was stirred at −78° C. for 1 hour. A solution of carbontetrabromide (2.36 g, 7.12 mmol) in THF (6.3 mL) was added drop wise andthe reaction was stirred at −78° C. for a further 1 hour. The reactionwas quenched by the addition of saturated aqueous ammonium chloride. Themixture was extracted with iso-hexane (×2) and the combined extractswashed with saturated aqueous sodium chloride. The solution was driedover anhydrous MgSO4 and concentrated to a brown oil. The crude materialwas purified by automated column chromatography, eluting withiso-hexane. Fractions found to contain pure product were combined andsolvent removed in vacuo to afford the desired compound as a yellow gumthat solidified on standing, 0.97 g, 91.7%.

Step 4: Preparation of 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine

Tetrabutylammonium fluoride solution, 1.0M in THF (2.61 mL, 2.61 mmol)was added to a solution of5-bromo-4-fluoro-1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridine(970 mg, 2.61 mmol) in THF (16.5 mL) at RT. The reaction mixture wasstirred at RT for 20 minutes and then partitioned between H₂O and Et₂O.The organic layer was separated and the aqueous was extracted with moreEt₂O (2×25 mL). The combined organic phases were washed with saturatedaqueous sodium chloride, dried (MgSO₄) and concentrated in vacuo toafford a brown gum.

The crude material was purified by automated chromatography, elutingwith iso-hexane to 40% EtOAc/iso-hexane (gradient). Fractions found tocontain pure product were combined and solvent removed in vacuo toafford the desired compound as an off white solid, 0.323 g, 57.5%.

Step 5: Preparation of5-Bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine

5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (0.323 g, 1.50 mmol) wasadded in portions to fuming nitric acid (1.6 mL) at 0° C. After additionthe reaction mixture was stirred at 0° C. for 30 minutes and then addedcarefully to rapidly stirring ice/H₂O (25 mL). The suspension wasstirred for a further 30 minutes and then the solids were collected viafiltration and the filter cake washed with copious amounts of H₂O andthen iso-hexane, prior to drying in vacuo at 60° C. This yielded thedesired compound as an off white solid, 0.335 g, 85.8%.

Step 6: Preparation of5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylamine

Tin (II) chloride dihydrate (2.62 g, 13.8 mmol) was added in portions to5-Bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.717 g, 2.76 mmol)in 6N HCl (21 mL) at 0° C. and then the cooling was removed and thereaction stirred at RT for 1 hour. The reaction mixture was cooled andpoured onto a mixture of ice/H₂O (50 mL) and basified to pH 8 by thecareful addition of 50% sodium hydroxide solution. This was extractedwith DCM/isopropyl alcohol (3:1; v:v) (3×100 mL) and the combinedextracts were washed with saturated aqueous sodium chloride, dried(MgSO₄) and concentrated in vacuo to afford a brown solid. This yieldedthe desired compound as a brown solid, 0.613 g, 96.5%.

Step 7: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

This was prepared using the methodology described for Example 1, Step 3,0.85 g, 77.0%.

Step 8: Preparation of Title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (40 mg, 0.10mmol), (R)-piperidin-3-yl-carbamic acid tert-butyl ester (97 mg, 0.48mmol) and n-butanol (2 mL) were combined in a 2-5 mL microwave vial. Thecontents were heated at 160° C. for 8 hours under microwave irradiationand then the reaction mixture was concentrated in vacuo. The residue wastaken up in DCM (3 mL) then TFA (3 mL) was added at RT and stirringcontinued for 3 hours. The solvent was removed in vacuo and the residuetaken up in EtOAc (20 mL), that was washed with saturated aqueous sodiumhydrogen carbonate (3×20 mL) and saturated aqueous sodiumchloridesaturated aqueous sodium chloride (50 mL). The organics weredried (MgSO₄) and concentrated in vacuo to afford a dark yellow gum.This crude material was purified by automated chromatography, elutingwith DCM to 10% MeOH/DCM (gradient). Fractions found to contain pureproduct were combined and concentrated in vacuo to afford the titlecompound as a pale yellow solid, 10.2 mg, 21.4%.

LC/MS: RT=1.77 Min (270 nm), m/z=494.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.13-1.20 (m, 1H), 1.44-1.53 (m, 1H), 1.62-1.77 (m,2H), 2.88-2.98 (m, 2H), 3.10-3.19 (m, 2H), 5.42 (s, 2H), 7.26-7.40 (m,5H), 7.71 (s, 1H), 8.04 (s, 1H), 8.19 (s, 1H), 8.52 (s, 1H), 9.77 (br s,1H), 11.71 (s, 1H) 3 protons not seen

Example 7 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-Pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (cream solid, 50.6 mg, 54.5%) was prepared asdescribed in Example 6, substituting (R)-pyrrolidin-3-yl-carbamic acidtert-butyl ester (180 mg, 0.97 mmol) for (R)-piperidin-3-yl-carbamicacid tert-butyl ester in Step 8.

LC/MS: RT=1.73 Min (254 nm), m/z=480.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.68-1.75 (m, 1H), 1.78-1.87 (br s, 2H), 2.12-2.21(m, 1H), 3.00-3.03 (m, 1H), 3.39-3.45 (m, 1H), 3.52-3.58 (m, 2H),3.66-3.70 (m, 1H), 5.39 (s, 2H), 7.28-7.40 (m, 5H), 7.78 (s, 1H), 8.10(s, 1H), 8.25 (s, 1H), 8.67 (s, 1H), 9.81 (br s, 1H), 11.63 (s, 1H)

Example 8 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-methylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (cream solid, 63.4 mg, 51.7%) was prepared asdescribed in Example 6, substituting carbamic acid,N-methyl-N-(3R)-3-piperidinyl-, 1,1-dimethylethyl ester (259 mg, 1.21mmol) for (R)-piperidin-3-yl-carbamic acid tert-butyl ester in Step 8.

LC/MS: RT=1.78 Min (270 nm), m/z=510.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.28-1.35 (m, 1H), 1.47-1.52 (m, 1H), 1.62-1.68 (m,1H), 1.72-1.79 (m, 1H), 2.10 (s, 3H), 2.56-2.61 (m, 1H), 2.95-2.99 (m,1H), 3.09-3.18 (m, 1H), 3.21-3.27 (m, 1H), 3.45-3.52 (m, 1H), 5.42 (s,2H), 7.26-7.39 (m, 5H), 7.79 (s, 1H), 8.07 (s, 1H), 8.19 (s, 1H), 8.47(s, 1H), 9.82 (br s, 1H), 11.70 (s, 1H) 1 proton not seen

Example 9 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-ethylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (cream solid, 34.8 mg, 39.4%) was prepared asdescribed in Example 6, substituting carbamic acid,N-ethyl-N-(3R)-3-piperidinyl-, 1,1-dimethylethyl ester (116 mg, 0.51mmol) for (R)-piperidin-3-yl-carbamic acid tert-butyl ester in Step 8.

LC/MS: RT=1.81 Min (270 nm), m/z=524.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 0.87 (t, 3H), 1.23-1.28 (m, 1H), 1.50-1.56 (m, 1H),1.71-1.73 (m, 2H), 2.45 (q, 2H), 2.72-2.78 (m, 1H), 2.99-3.05 (m, 1H),3.14-3.21 (m, 2H), 5.42 (s, 2H), 7.26-7.39 (m, 5H), 7.71 (s, 1H), 8.06(s, 1H), 8.20 (s, 1H), 8.45 (s, 1H), 9.70 (br s, 1H), 11.73 (s, 1H) 2protons not seen

Example 10 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-hydroxy-pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (pale orange solid, 47 mg, 51.0%) was prepared asdescribed in Example 6, substituting (R)-pyrrolidin-3-ol (84 mg, 0.97mmol) for (R)-piperidin-3-yl-carbamic acid tert-butyl ester in Step 8.

LC/MS: RT=2.30 Min (270 nm), m/z=483.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.94-1.99 (m, 1H), 2.24-2.33 (m, 1H), 3.14-3.17 (m,1H), 3.43-3.49 (m, 1H), 3.53-3.60 (m, 1H), 3.64-3.68 (m, 1H), 4.54 (brs, 1H), 5.37 (s, 2H), 5.50 (d, 1H), 7.29-7.39 (m, 5H), 7.85 (s, 1H),8.14 (s, 1H), 8.27 (s, 1H), 8.60 (s, 1H), 9.72 (br s, 1H), 11.63 (s, 1H)

Example 11 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-hydroxy-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (pale yellow solid, 3.6 mg, 6.0%) was prepared asdescribed in Example 6, substituting (R)-3-hydroxypiperidinehydrochloride (83 mg, 0.6 mmol) for (R)-piperidin-3-yl-carbamic acidtert-butyl ester and using potassium carbonate (83 mg, 0.6 mmol) as basein Step 8.

LC/MS: RT=2.35 Min (270 nm), m/z=495.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.48-1.54 (m, 2H), 1.63-1.68 (m, 1H), 1.78-1.87 (m,1H), 2.97-3.07 (m, 2H), 3.54-3.63 (m, 1H), 3.84-3.90 (m, 1H), 5.33 (brs, 1H), 5.39 (s, 2H), 7.26-7.39 (m, 5H), 7.88 (s, 1H), 8.18 (s, 1H),8.20 (s, 1H), 8.62 (s, 1H), 9.91 (br s, 1H), 11.69 (s, 1H) 1 proton notseen

Example 12 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-(3-dimethylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (pale yellow solid, 51.9 mg, 54.9%) was prepared asdescribed in Example 6, substituting dimethyl-piperidin-3-yl-amine (116mg, 0.91 mmol) for (R)-piperidin-3-yl-carbamic acid tert-butyl ester inStep 8.

LC/MS: RT=1.78 Min (270 nm), m/z=524.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.31-1.37 (m, 1H), 1.54-1.58 (m, 1H), 1.63-1.75 (m,2H), 1.99 (s, 6H), 2.21-2.25 (m, 1H), 3.10-3.19 (m, 3H), 4.26-4.46 (m,1H), 5.41 (s, 2H), 7.25-7.27 (m, 2H), 7.30-7.39 (m, 3H), 7.70 (s, 1H),8.07 (s, 1H), 8.20 (s, 1H), 8.42 (s, 1H), 9.61 (br s, 1H), 11.73 (s, 1H)

Example 13 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-bromo-4-[(R)-3-(cyclopentylmethyl-amino)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared from Example 61-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (40.0 mg, 0.08 mmol),acetic acid (0.01 mL, 0.17 mmol) and cyclopentanecarbaldehyde (10.8 mg,0.11 mmol) were stirred in MeOH (0.5 mL). Reaction mixture was stirredat RT for 10 minutes before addition of NaBH(OAc)₃ (42.4 mg, 0.2 mmol)and reaction mixture was left to stir at RT 18 hours. The reactionmixture was basified with sodium bicarbonate solution and extracted withEtOAc (3×30 mL). The organic phases were combined, washed with saturatedaqueous sodium chloride, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by automated column chromatography, eluting withDCM to 5% MeOH/DCM (gradient). Fractions found to contain pure productwere combined and concentrated in vacuo to afford the title compound asa yellow solid, 5.6 mg, 12.1%.

LC/MS: RT=2.00 Min (230 nm), m/z=576.6 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 0.94-1.80 (m, 14H), 2.24-2.32 (m, 2H), 2.59-2.66 (m,1H), 2.93-3.68 (m, 3H), 5.41 (s, 2H), 7.25-7.26 (m, 2H), 7.30-7.39 (m,3H), 7.68 (d, 1H), 8.03 (s, 1H), 8.19 (s, 1H), 8.42 (s, 1H), 9.66 (br s,1H), 11.72 (d, 1H)

Example 14 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-isobutylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (cream solid, 38.1 mg, 68.4%) was prepared asdescribed in Example 13, substituting isobutyraldehyde (9.9 mg, 0.14mmol) for cyclopentanecarbaldehyde.

LC/MS: RT=1.91 Min (254 nm), m/z=552.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 0.74 (d, 6H), 1.14-1.20 (m, 1H), 1.40-1.50 (m, 1H),1.52-1.58 (m, 1H), 1.69-1.71 (m, 2H), 2.13-2.22 (m, 2H), 2.58-2.62 (m,1H), 2.95-3.00 (m, 1H), 3.10-3.15 (m, 1H), 3.21-3.27 (m, 1H), 5.42 (s,2H), 7.25-7.27 (m, 2H), 7.30-7.39 (m, 3H), 7.66 (d, 1H), 8.02 (s, 1H),8.19 (s, 1H), 8.41 (s, 1H), 9.62 (br s, 1H), 11.73 (br s, 1H) 2 protonsnot seen

Example 15 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-bromo-4-[(R)-3-(2,2-dimethyl-propylamino)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound (cream solid, 38.1 mg, 68.4%) was prepared asdescribed in Example 13, substituting isobutyraldeyhyde (9.9 mg, 0.14mmol) for cyclopentanecarbaldehyde.

LC/MS: RT=1.96 Min (270 nm), m/z=566.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 0.75 (s, 9H), 1.08-1.13 (m, 2H), 1.53-1.58 (m, 1H),1.63-1.74 (m, 2H), 2.10-2.17 (m, 2H), 2.97-3.08 (m, 2H), 5.41 (s, 2H),7.23-7.26 (m, 2H), 7.30-7.39 (m, 3H), 7.58 (s, 1H), 8.00 (s, 1H), 8.19(s, 1H), 8.39 (s, 1H), 9.52 (br s, 1H), 11.74 (s, 1H) 3 protons not seen

Example 16 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-bromo-4-[(R)-3-(cyclopropylmethyl-amino)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound (cream solid, 18.4 mg, 41.9%) was prepared asdescribed in Example 13, substituting cyclopropylcarboxaldehyde (7.7 mg,0.14 mmol) for cyclopentanecarbaldehyde.

LC/MS: RT=1.88 Min (254 nm), m/z=550.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 0.09-0.02 (m, 2H), 0.23-0.26 (m, 2H), 0.64-0.71 (m,1H), 1.25-1.30 (m, 1H), 1.51-1.56 (m, 1H), 1.68-1.77 (m, 2H), 2.18-2.29(m, 2H), 2.71-2.77 (m, 1H), 2.96-3.03 (m, 1H), 3.16-3.28 (m, 2H), 5.42(s, 2H), 7.25-7.27 (m, 2H), 7.30-7.39 (m, 3H), 7.73 (s, 1H), 8.05 (s,1H), 8.19 (s, 1H), 8.47 (s, 1H), 9.74 (br s, 1H), 11.71 (s, 1H) 2protons not seen

Example 17 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 6, substituting1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (157 mg, 0.715 mmol)for 1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 7.

Preparation of 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid

Ethyl 4-pyrazolecarboxylate (1.5 g, 10.7 mmol) and K₂CO₃ (4.44 g, 32.1mmol) were stirred in acetone (45 mL). To this was added 4-fluorobenzylbromide (1.38 mL, 11.24 mmol) and the reaction mixture was heated at 50°C. for 18 hours. The reaction was cooled to RT and the solids separatedvia filtration. The filter cake was washed through with EtOAc and thefiltrate concentrated in vacuo. The residue was taken up in MeOH (36 mL)and a solution of KOH (1.20 g, 21.4 mmol) in water (7.2 mL) was added.The reaction was refluxed for 2 hours, cooled and the solvent removed invacuo. The residue was diluted with a little H₂O, cooled to 5° C., andacidified by the careful addition of 1M HCl solution to precipitate theproduct. After stirring for 10 minutes the solids were collected viafiltration, washed well with water, iso-hexane and dried in vacuo at 40°C. for 18 hours to afford 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylicacid as a white solid, 2.35 g, 99.6%.

The title compound was isolated as a pale yellow solid, 20.5 mg, 17.3%.

LC/MS: RT=1.80 Min (254 nm), m/z=514.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.12-1.25 (m, 1H), 1.43-1.53 (m, 1H), 1.65-1.75 (m,2H), 1.95-2.30 (br s, 2H), 2.87-3.00 (m, 2H), 3.01-3.20 (m, 2H), 5.41(s, 2H), 7.21 (dd, 2H), 7.33 (dd, 2H), 7.71 (s, 1H), 8.04 (s, 1H), 8.19(s, 1H), 8.51 (br s, 1H), 9.75 (br s, 1H), 11.70 (br s, 1H) 1 proton notseen

Example 18 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (pale yellow solid, 19.6 mg, 17.3%) was prepared asdescribed in Example 6, substituting1-(4-chloro-benzyl)-1H-pyrazole-4-carboxylic acid (163 mg, 0.715 mmol),prepared in a similar manner to that described for1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, for1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 7.

LC/MS: RT=1.87 Min (254 nm), m/z=530.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.11-1.20 (m, 1H), 1.43-1.79 (m, 5H), 2.86-2.98 (m,2H), 3.09-3.20 (m, 2H), 5.42 (s, 2H), 7.28 (d, 2H), 7.44 (d, 2H), 7.71(s, 1H), 8.05 (s, 1H), 8.19 (s, 1H), 8.53 (br s, 1H), 9.77 (br s, 1H),11.72 (br s, 1H) 1 proton not seen

Example 19 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (tan solid, 22 mg, 18.5%) was prepared as describedin Example 6, substituting 1-(4-methyl-benzyl)-1H-pyrazole-4-carboxylicacid (155 mg, 0.715 mmol), prepared in a similar manner to thatdescribed for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, for1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 7. LC/MS: RT=1.85 Min(254 nm), m/z=508.4 [M+H]. Total run time 3.75 min (short pos/neg),HP1100.

¹H NMR (d₆ DMSO): δ 1.11-1.25 (m, 1H), 1.43-1.53 (m, 1H), 1.65-1.77 (m,2H), 2.13-2.70 (br s, 2H), 2.29 (s, 3H), 2.88-3.01 (m, 2H), 3.08-3.20(m, 2H), 5.36 (s, 2H), 7.15-7.21 (m, 4H), 7.70 (s, 1H), 8.02 (s, 1H),8.19 (s, 1H), 8.47 (br s, 1H), 9.74 (br s, 1H), 11.70 (br s, 1H) 1proton not seen

Example 20 1-(4-Methoxy-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (tan solid, 16.2 mg, 13.7%) was prepared as describedin Example 6, substituting 1-(4-methoxy-benzyl)-1H-pyrazole-4-carboxylicacid (166 mg, 0.715 mmol), prepared in a similar manner to thatdescribed for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, for1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 7.

LC/MS: RT=1.79 Min (254 nm), m/z=524.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.10-1.27 (m, 1H), 1.43-1.53 (m, 1H), 1.64-1.95 (m,4H), 2.87-2.99 (m, 2H), 3.09-3.21 (m, 2H), 3.74 (s, 3H), 5.32 (s, 2H),6.92 (d, 2H), 7.25 (d, 2H), 7.72 (s, 1H), 8.01 (s, 1H), 8.19 (s, 1H),8.44 (br s, 1H), 9.73 (br s, 1H), 11.69 (br s, 1H) 1 proton not seen

Example 21 1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (yellow solid, 40 mg, 68.7%) was prepared asdescribed in Example 6, substituting1-pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid (150 mg, 0.74 mmol),prepared in a similar manner to that described for1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid in Example 81, Step1, for 1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 7. It wasisolated as a formate salt following purification by preparative HPLC atpH4.

LC/MS: RT=0.87 Min (270 nm), m/z=497 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): d □1.21-1.34 (br m, 1H), 1.40-1.53 (br m, 1H),1.59-1.68 (br m, 1H), 1.78-1.86 (br m, 1H), 2.98-3.08 (br m, 1H),3.13-3.29 (br m, 3H), 3.33-3.44 (br m, 1H), 5.52 (s, 2H), 7.10 (d, 1H),7.31-7.35 (m, 1H), 7.54 (s, 1H), 7.78-7.82 (m, 1H), 8.06 (s, 1H), 8.20(s, 1H), 8.49-8.56 (m, 2H), 9.77 (br s, 1H) 3 protons not seen

Example 22 1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (tan solid, 9.5 mg, 38%) was prepared as described inExample 6, substituting 1-pyridin-3-ylmethyl-1H-pyrazole-4-carboxylicacid (150 mg, 0.74 mmol) prepared in a similar manner to that describedfor 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid in Example 81,Step 1, for 1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 7.

LC/MS: RT=0.83 Min (270 nm), m/z=497 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): d 1.43-1.55 (br m, 1H), 1.61-1.69 (br m, 1H),1.72-1.79 (br m, 1H), 3.03-3.22 (br m, 4H), 5.48 (s, 2H), 7.39-7.43 (m,1H), 7.61 (s, 1H), 7.66-7.69 (m, 1H), 8.05 (s, 1H), 8.22 (s, 1H),8.50-8.55 (m, 3H), 9.61 (br s, 1H), 11.81 (br s, 1H) 4 protons not seen

Example 23 1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (tan solid, 25 mg, 24%) was prepared as described inExample 6, substituting 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylicacid (225 mg, 1.1 mmol), described in Example 81, Step 1, for1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 7.

LC/MS: RT=0.74 Min (254 nm), m/z=no mass [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): d □ 1.10-1.20 (br m, 1H), 1.44-1.54 (br m, 1H),1.61-1.80 (br m, 2H), 2.87-2.99 (br m, 2H), 3.09-3.23 (br m, 2H), 5.51(s, 2H), 7.15 (d, 2H), 7.72 (s, 1H), 8.10 (s, 1H), 8.20 (s, 1H), 8.55(d, 2H), 8.59 (s, 1H), 9.82 (s, 1H), 11.72 (br s, 1H) 4 protons not seen

Example 24N-{4-[(3R)-3-aminopiperidin-1-yl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-1-benzyl-1H-pyrazole-4-carboxamide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2.

The title compound was prepared as described in Example 6, Steps 1 and2.

Step 3: 5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine

4-Fluoro-1-[tris(propan-2-yl)silyl]-1H-pyrrolo[2,3-b]pyridine (2 g, 6.84mmol) in THF (80 mL) at −78° C. was treated drop wise withsec-butyllithium solution, 1.4M in cyclohexane (4.48 mL, 6.27 mmol). Thereaction was stirred at −78° C. for 0.5 hours. A solution ofhexachloroethane (4.05 g, 17.1 mmol) in THF (20 mL) was added drop wiseand the reaction was stirred at −78° C. for a further 0.5 hours. Thereaction was quenched by the addition of saturated aqueous ammoniumchloride. The mixture was extracted with iso-hexane (×2) and thecombined extracts washed with saturated aqueous sodium chloride. Thesolution was dried over anhydrous MgSO4 and concentrated to a yellowgum.

The crude material was stirred in THF (50 mL) and tetrabutylammoniumfluoride solution, 1.0M in THF (6.84 mL, 6.84 mmol) was added drop wiseat RT. The reaction was stirred at RT for a further 1 hour before H₂Oand EtOAc were added. The organic layer was separated and the aqueousphase was extracted with another portion of EtOAc. The combined organicphases were washed with saturated aqueous sodium chloride, dried (MgSO₄)and concentrated in vacuo to afford a pale orange solid. The cruderesidue was purified by automated flash chromatography eluting withiso-hexane to 40% EtOAc/iso-hexane. Fractions containing pure materialwere combined and solvent removed in vacuo to afford the desired productas a white solid 1.0 g, 85.7%.

Step 4: Preparation of5-chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine

This was prepared using the methodology described for Example 6, Step 5,substituting 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1 g, 5.86mmol) for 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine. The title compoundwas isolated as a white solid, 1.15 g, 91.1%.

Step 5: Preparation of5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylamine

This was prepared using the methodology described for Example 6, Step 6,substituting 5-chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (202.9mg, 0.94 mmol) for 5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine.The title compound was isolated as a solid, 167.4 mg, 95.8%.

Step 6: Preparation of 1-benzyl-1H-pyrazole-4-carboxylic acid(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylamine (167.4 mg, 0.90mmol) was stirred in DMF (9.0 mL) with Et₃N (0.25 mL, 1.80 mmol) and1-benzyl-1H-pyrazole-4-carboxylic acid (200.6 mg, 0.99 mmol). HATU(342.2 mg, 0.90 mmol) was added and the reaction was stirred at RT for 2hours. The reaction mixture was diluted with H₂O, and extracted withEtOAc (3×30 mL). The combined extracts were washed with saturatedaqueous sodium bicarbonate, saturated aqueous sodium chloride (4×60 mL),dried (MgSO₄) and solvent removed in vacuo to afford a brown gum. Thiswas triturated with Et₂O, filtered and washed with Et₂O prior to dryingin vacuo at 40° C. This afforded the title compound as an off whitesolid, 240.5 mg, 72.1%.

Step 7: Preparation of title compound:N-{4-[(3R)-3-aminopiperidin-1-yl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-1-benzyl-1H-pyrazole-4-carboxamide

A solution of 1-benzyl-1H-pyrazole-4-carboxylic acid(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (100.0 mg, 0.27mmol) in n-BuOH (5.4 mL) was treated with (R)-piperidin-3-yl-carbamicacid tert-butyl ester (270.8 mg, 1.35 mmol) and heated under microwaveirradiation at 160° C. for 6 hours. The solvent was removed in vacuo andresidue was taken up in DCM (5 mL). TFA (5 mL) was added and thereaction stirred at RT for 18 hours. The reaction mixture wasconcentrated in vacuo, the residue taken up in EtOAc (40 mL), washedwith aqueous ammonia solution (2×50 mL), saturated aqueous sodiumchloride, dried (MgSO₄) and concentrated in vacuo. The crude materialwas purified by automated column chromatography, eluting with DCM to 10%MeOH/DCM (gradient). The fractions containing pure product were combinedand concentrated in vacuo to afford the title compound as a cream solid,53.6 mg, 44.1%.

LC/MS: RT=1.77 Min (270 nm), m/z=450.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.16-1.21 (m, 1H), 1.45-1.49 (m, 1H), 1.66-1.74 (m,4H), 2.90-2.94 (m, 2H), 3.13-3.16 (m, 2H), 5.42 (s, 2H), 7.26-7.39 (m,5H), 7.73 (s, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.53 (s, 1H), 9.73 (br s,1H), 11.68 (s, 1H) 1 proton not seen

Example 25 1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (cream solid, 24 mg, 28.4%) was prepared as describedin Example 24, substituting 1-(4-methyl-benzyl)-1H-pyrazole-4-carboxylicacid (256.3 mg, 1.19 mmol) for 1-benzyl-1H-pyrazole-4-carboxylic acid,in Step 6.

LC/MS: RT=1.82 Min (254 nm), m/z=464 [M+H]. Total run time 3.75 min(short pos) HP1100.

¹H NMR (d₆ DMSO): □□, 1.18 (m, 1H), 1.52 (m, 2H), 1.68 (m, 2H), 2.33 (2,3H), 2.91 (m, 2H), 3.14 (m, 2H), 3.33 (m, 2H), 5.36 (s, 2H), 7.19 (m,4H), 7.75 (s, 1H), 8.03 (s, 1H), 8.09 (s, 1H), 8.50 (s, 1H), 9.73 (s,1H), 11.69 (s, 1H)

Example 26 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (cream solid, 24.2 mg, 20.1%) was prepared asdescribed in Example 24, substituting1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (261 mg, 1.19 mmol)for 1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 6.

LC/MS: RT=1.77 Min (270 nm), m/z=468.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.18-1.23 (m, 1H), 1.45-1.50 (m, 1H), 1.68-1.70 (m,2H), 2.94-2.99 (m, 2H), 3.11-3.13 (m, 2H), 5.41 (s, 2H), 7.19-7.23 (m,2H), 7.32-7.36 (m, 2H), 7.71 (s, 1H), 8.04 (s, 1H), 8.09 (s, 1H), 8.51(s, 1H), 9.69 (br s, 1H), 11.71 (br s, 1H) 3 protons not seen

Example 27 1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (cream solid, 22.1 mg, 18.4%) was prepared asdescribed in Example 24, substituting1-(4-chloro-benzyl)-1H-pyrazole-4-carboxylic acid (280.5 mg, 1.19 mmol)for 1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 6.

LC/MS: RT=1.84 Min (270 nm), m/z=484.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.15-1.20 (m, 1H), 1.45-1.49 (m, 1H), 1.66-1.72 (m,2H), 2.92-2.96 (m, 2H), 3.13-3.16 (m, 2H), 5.42 (s, 2H), 7.29 (d, 2H),7.44 (d, 2H), 7.72 (s, 1H), 8.05 (s, 1H), 8.09 (s, 1H), 8.53 (s, 1H),9.72 (br s, 1H), 11.70 (br s, 1H) 3 protons not seen

Example 28 1-(4-Methoxy-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (white solid, 24 mg, 19.8%) was prepared as describedin Example 24, substituting1-(4-methoxy-benzyl)-1H-pyrazole-4-carboxylic acid (275.3 mg, 1.19 mmol)for 1-benzyl-1H-pyrazole-4-carboxylic acid, in Step 6.

LC/MS: RT=1.77 Min (254 nm), m/z=480 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.17 (m, 1H), 1.49 (m, 2H), 1.71 (m, 2H), 2.91 (m,2H), 3.14 (m, 2H), 3.33 (m, 2H), 3.75 (s, 3H), 5.33 (s, 2H), 6.94 (d, J8.68, 2H), 7.27 (d, J 8.65, 2H), 7.75 (s, 1H), 8.01 (s, 1H), 8.08 (s,1H), 8.46 (s, 1H), 9.71 (s, 1H), 11.65 (s, 1H)

Example 29 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-Pyrrolidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound (white solid, 42.5 mg, 60.1%) was prepared asdescribed in Example 24, substituting (R)-pyrrolidin-3-yl-carbamic acidtert-butyl ester (151.1 mg, 0.81 mmol) for (R)-piperidin-3-yl-carbamicacid tert-butyl ester, in Step 7.

LC/MS: RT=1.71 Min (254 nm), m/z=436.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.66-1.72 (m, 1H), 2.09-2.17 (m, 1H), 3.02-3.05 (m,1H), 3.37-3.43 (m, 1H), 3.51-3.58 (m, 2H), 3.63-3.68 (m, 1H), 5.39 (s,2H), 7.28-7.39 (m, 5H), 7.76 (s, 1H), 8.10 (s, 1H), 8.14 (s, 1H), 8.66(s, 1H), 9.78 (s, 1H), 11.60 (br s, 1H) 2 protons not seen

Example 30N-{4-[(3R)-3-aminopiperidin-1-yl]-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-1-benzyl-1H-pyrazole-4-carboxamide

The title compound was prepared from((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester, the product of Step 1, Example 53.

((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (29 mg, 0.05 mmol), cyclopropylboronic acid (8.4mg, 0.1 mmol), Pd(dppf)Cl₂ (5.1 mg, 0.01 mol) and K₂CO₃ (27.6 mg, 0.20mmol) and THF (4.5 mL)/H₂OH₂O (0.5 mL) were charged to a microwave vialand degassed. The contents were heated under microwave irradiation at120° C. for 1 hour. The reaction mixture was partitioned between EtOAcand H₂OH₂O, then the organic layer was separated and the aqueousextracted with another portion of EtOAc. The combined organics werewashed with saturated aqueous sodium hydrogen bicarbonate, H₂OH₂O,saturated aqueous sodium chloride, dried (MgSO₄) and solvent removed invacuo to give crude((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester as a yellow oil.

This material was taken up in hydrochloric acid solution, 1.25 M in MeOH(5 mL) and irradiated in a microwave for 1 hour at 80° C. The volatileswere removed in vacuo and the residue was taken up in the minimum volumeof MeOH and loaded onto a SCX2 ion exchange column that had been primedwith MeOH. The column was washed with DCM, MeOH and the title compoundwas eluted using ammonia solution, 3.5M in MeOH. This solution wasconcentrated in vacuo and the residue was purified by preparative HPLCat pH4 and then at pH9. The material was taken up in acetone andfiltered through a plug of potassium carbonate. The filtrate wasconcentrated in vacuo to afford the title compound as a solid, 1.5 mg,6.8%.

LC/MS: RT=1.56 Min (270 nm), m/z=456 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₄ MeOH): δ 0.72-1.07 (m, 4H), 1.20-2.18 (m, 5H), 3.16-3.24 (m,1H), 3.37-3.52 (m, 3H), 5.41 (s, 2H), 7.28-7.42 (m, 5H), 7.66 (s, 1H),7.96 (s, 1H), 8.10 (s, 1H), 8.32 (s, 1H) 5 protons not seen

Example 31 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 9. The title compound was prepared as described in Example 6. InStep 3, (2R,8aS)-(+)-(camphorylsulfonyl)oxaziridine (2.55 g, 11.1 mmol)was used as the electrophile instead of carbon tetrabromide. Followingthe usual work up, purification by flash column chromatography elutingwith iso-hexane and then 5% EtOAc/iso-hexane, the desired intermediate,4-fluoro-1-triisopropylsilanyl-1H-indol-5-ol, was isolated as a paleyellow oil, 0.91 g, 66.5%.

Step 4: Preparation of 2,2-dimethyl-propionic acid4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl ester

To a solution of 4-fluoro-1-triisopropylsilanyl-1H-indol-5-ol (1 g, 3.24mmol) and Et₃N (0.45 mL, 3.24 mmol) in DCM (1 mL) was added pivaloylchloride (0.8 mL, 6.5 mmol) and stirred at RT for 3 hours. The mixturewas diluted with DCM (30 mL) and washed with H₂O, saturated aqueoussodium chloride, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The crude material was purified by flash column chromatography to givethe title compound as a clear oil, 0.55 g, 43.2%.

Step 5: Preparation of 2,2-dimethyl-propionic acid4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl ester

Tetrabutylammonium fluoride solution, 1.0M in THF (2.8 mL, 2.8 mmol) wasadded drop wise to a solution of 2,2-dimethyl-propionic acid4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl ester (550mg, 1.4 mmol) in THF (10 mL) at 0° C. After addition, stirring wascontinued for a further 1.5 hours at RT. EtOAc was added and the mixturewashed with H₂O and saturated aqueous sodium chloride. The organics weredried over MgSO₄, concentrated in vacuo and the crude material obtainedwas purified by flashchromatography eluting with 33% EtOAc/iso-hexane.Fractions containing pure product were combined and concentrated invacuo to afford the title compound as a white solid, 270 mg, 81.6%.

Step 6: Preparation of 2,2-dimethyl-propionic acid4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridin-5-yl ester

This was prepared using the methodology described for Example 6, Step 5,substituting 2,2-dimethyl-propionic acid4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl ester (270 mg, 1.14 mmol) for5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine. The title compound wasisolated as a pale yellow solid, 321 mg, 99.9%.

Step 7: Preparation of 2,2-dimethyl-propionic acid4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridin-5-ylester

2,2-Dimethyl-propionic acid4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridin-5-yl ester (95 mg, 0.34 mmol),(R)-piperidin-3-yl-carbamic acid tert-butyl ester (81 mg, 0.4 mmol),DIPEA (89 uL, 0.51 mmol) and 1-butanol (2 mL) were combined in amicrowave vial and then heated at 120° C. for 2 hours under microwaveirradiation. The mixture was concentrated in vacuo and the residuepurified by flashchromatography eluting with 25% EtOAc/iso-hexane.Fractions containing product were combined and concentrated in vacuo togive the title compound as a yellow solid 73 mg, 46.5%.

Step 8: Preparation of 2,2-dimethyl-propionic acid3-amino-4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylester

To a mixture of 2,2-dimethyl-propionic acid4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridin-5-ylester (73 mg, 0.158 mmol) and Et₃N (0.2 mL) in MeOH (20 mL) was addedRaney Nickel, 50% slurry in H₂O (10 mg). The reaction was stirred at RTan atmosphere of hydrogen for 18 hours. The catalyst was removed viafiltration and the filtrate concentrated in vacuo to afford the titlecompound as a brown solid, 68 mg, 100%.

Step 9: Preparation of 2,2-dimethyl-propionic acid3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylester

2,2-Dimethyl-propionic acid3-amino-4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylester (68 mg, 0.158 mmol) and 1-benzyl-1H-pyrazole-4-carboxylic acid (32mg, 0.158 mmol) were stirred in DMF (5 mL) at RT. To this was addedtriethylamine (0.04 mL, 5.74 mmol) followed by HATU (60 mg, 0.158 mmol)and the mixture was stirred at room temperature for 5 hours. Theresulting solution was concentrated in vacuo and the resultant brown gumwas taken up in EtOAc (100 mL). It was washed with H₂O (2×60 mL),saturated aqueous sodium chloride (20 mL), dried (MgSO₄) andconcentrated in vacuo. The crude material was purified by flash columnchromatography to afford the title compound as a brown solid, 63 mg,64.8%.

Step 10: Preparation of((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester

To a solution of 2,2-dimethyl-propionic acid3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylester (382 mg, 0.62 mmol, in ethanol (15 mL) was added aqueous NaOH, 4N(1.5 mL, 6 mmol) and the reaction was stirred at RT for 2 hours. Thesolvent was removed in vacuo and the residue was carefully neutralizedto pH7 with HCl, 6N. The mixture was extracted with EtOAc (3×40 mL) andthe combined extracts washed with saturated aqueous sodium chloride(×3), dried over Na₂SO₄ and concentrated in vacuo. The crude materialwas purified twice by flash column chromatography eluting with 6%MeOH/DCM and the fractions containing pure product were combined andconcentrated in vacuo to give the title compound as a pale brown solid115 mg, 34.9%.

Step 11: Preparation of title compound:1-benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

((R)-1-{3-[(1-Benzyl-1H-pyrazole-4-carbonyl)-amino]-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (115 mg, 0.216 mmol) was stirred in MeOH (4 mL)and hydrochloric acid solution, 4N in MeOH (1 mL) was added. The mixturewas stirred at RT for 18 hours and then neutralized (pH 7) by thecareful addition of ammonium hydroxide solution. DCM (70 mL) was addedand the mixture washed with H₂O (2×20 mL), saturated aqueous sodiumchloride (2×20 mL), dried over Na₂SO₄ and concentrated in vacuo toafford the title compound as the hydrochloride salt, 75 mg, 80.5%.

LC/MS: RT=2.02 Min (270 nm), m/z=432 [M+H]. Total run time 7.5 min (longpos), HP1100.

¹H NMR (d₆ DMSO): □ 1.35-1.48 (m, 2H), 1.59-1.69 (m, 1H), 1.84-1.91 (m,1H), 2.99-3.11 (m, 2H), 3.17-3.38 (m, 2H), 5.42 (s, 2H), 7.24-7.28 (m,2H), 7.30-7.40 (m, 3H), 7.50 (d, 1H), 7.88 (s, 1H), 7.99 (br s, 3H),8.02 (s, 1H), 8.42 (s, 1H), 9.31 (br s, 1H), 9.52 (s, 1H), 11.39 (s, 1H)1 proton not seen

Example 32 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared from4-fluoro-1-triisopropylsilanyl-1H-indol-5-ol, the product of Step 3, inExample 31.

Step 1: Preparation of4-Fluoro-5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine

Diisopropyl azodicarboxylate (688 mg, 3.4 mmol) was added drop wise to asolution of 4-fluoro-1-triisopropylsilanyl-1H-indol-5-ol (805 mg, 2.61mmol) and triphenylphosphine (892 mg, 3.44 mmol) in THF (25 mL) at 0° C.and the reaction stirred for 10 mins. MeOH (1 mL, 24.7 mmol) was addedand the mixture stirred for a further 1 hour at 0° C. and then RT for 1hour. The solution was concentrated in vacuo to a dark yellow gum. Thecrude material was purified by column chromatography eluting withiso-hexane to 3% EtOAc/iso-hexane. Fractions containing pure productwere combined and concentrated in vacuo to afford the title compound asa pale yellow oil, 680 mg, 80.8%.

Step 2: Preparation of 4-Fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridine

This was prepared using the methodology described for Example 31, Step5, substituting4-fluoro-5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (630mg, 1.95 mmol) for 2,2-dimethyl-propionic acid4-fluoro-1-triisopropylsilanyl-1 H-pyrrolo[2,3-b]pyridin-5-yl ester. Thetitle compound was isolated as a pale yellow solid, 285 mg, 87.8%.

Step 3: Preparation of4-Fluoro-5-methoxy-3-nitro-1H-pyrrolo[2,3-b]pyridine

This was prepared using the methodology described for Example 6, Step 5,substituting 4-fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridine (280 mg, 1.69mmol) for 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine. The title compoundwas isolated as a pale yellow solid, 325 mg, 91.3%.

Step 4: Preparation of[(R)-1-(5-methoxy-3-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester

This was prepared using the methodology described for Example 31, Step7, substituting 4-fluoro-5-methoxy-3-nitro-1H-pyrrolo[2,3-b]pyridine(270 mg, 1.28 mmol) for 2,2-dimethyl-propionic acid4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridin-5-yl ester. The title compoundwas isolated as a yellow solid, 385 mg, 76.9%.

Step 5: Preparation of[(R)-1-(3-amino-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester

This was prepared using the methodology described for Example 31, Step8, substituting[(R)-1-(5-methoxy-3-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester (130 mg, 0.332 mmol) for 2,2-dimethyl-propionicacid4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridin-5-ylester. The title compound was isolated as a brown oil, 120 mg, 100%.

Step 6: Preparation of((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester

This was prepared using the methodology described for Example 31, Step9, substituting[(R)-1-(3-amino-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester (120 mg, 0.332 mmol) for 2,2-dimethyl-propionicacid3-amino-4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylester. The title compound was isolated as a pale brown solid, 68 mg,37.5%.

Step 7: Preparation of title compound: 1-benzyl-1H-pyrazole-4-carboxylicacid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

To a solution of((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (320 mg, 0.58 mmol) in MeOH (10 mL) was addedhydrochloric acid solution, 3.0 M in MeOH (2 mL) at 0° C. After additionthe reaction mixture was stirred at 50° C. for 3 hours and thenconcentrated in vacuo. The residue was partitioned between saturatedaqueous sodium carbonate (15 mL) and 20% MeOH in DCM (100 mL). Theorganics were separated, washed with H₂O, saturated aqueous sodiumchloride and dried over anhydrous Na₂SO₄. The solvent was removed invacuo and the crude material purified by flash column chromatography togive the title compound as an off white solid, 105 mg, 73%.

LC/MS: RT=2.14 Min (270 nm), m/z=446 [M+H]. Total run time 7.5 min (longpos), HP1100.

¹H NMR (d₆ DMSO): δ 1.15-1.25 (m, 1H), 1.40-1.51 (m, 1H), 1.67-1.76 (m,2H), 2.25 (br s, 2H), 2.82-2.94 (m, 2H), 3.00-3.08 (m, 2H), 3.19-3.25(m, 1H), 3.85 (s, 3H), 5.41 (s, 2H), 7.25-7.40 (m, 5H), 7.71 (s, 1H),8.01 (s, 1H), 8.07 (s, 1H), 8.54 (s, 1H), 9.71 (br s, 1H), 11.22 (br s,1H).

Example 33 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared from((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester, the product of Step 1, Example 53.

((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (48.0 mg, 0.08 mMmol), methylboronic acid (8.70mg, 0.15 mMmol), Pd(dppf)Cl₂ (7.0 mg, 0.01 mMmol) and K₂CO₃ (22.1 mg,0.16 mMmol) and THF (4.5 mL)/H₂O (0.5 mL) were charged to a microwavevial and degassed. The contents were heated under microwave irradiationat 120° C. for 2 hours. The reaction mixture was partitioned betweenEtOAc and H₂O, then the organic layer was separated and the aqueousextracted with another portion of EtOAc. The combined organics werewashed with H₂O, saturated aqueous sodium chloride, dried (MgSO₄) andsolvent removed in vacuo. The crude product was purified by automatedcolumn chromatography eluting with iso-hexane to 15% EtOAc/iso-hexane(gradient). Fractions found to contain pure material were combined andsolvent removed in vacuo to afford((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester.

This was taken up in DCM (5 mL) and trifluoroacetic acid (0.05 mL, 0.6mMmol) was added drop wise and the reaction was allowed to stir for 2hours at RT. Trifluoroacetic acid (0.05 mL, 0.6 mMmol) was added and thereaction was stirred for a further 1 hour at RT. The volatiles wereremoved in vacuo and residue was partitioned between DCM and H₂O. Theorganic layer was separated and washed with saturated aqueous sodiumchloride, dried (MgSO₄) and the volatiles removed in vacuo. The residuewas purified by preparative HPLC at pH9, taken up in acetone andfiltered through a plug of potassium carbonate. The filtrate wasconcentrated in vacuo to afford the title compound as a solid, 4 mg,11.5%.

LC/MS: RT=1.61 Min (270 nm), m/z=430 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₄ MeOH) δ 1.11-1.23 (m, 1H), 1.50-1.64 (m, 1H), 1.69-1.76 (m,1H), 1.78-1.87 (m, 1H), 2.44 (s, 3H), 2.83-2.97 (m, 2H), 3.08-3.23 (m,2H), 5.42 (s, 2H), 7.28-7.41 (m, 5H), 7.62 (s, 1H), 7.93 (s, 1H), 8.04(s, 1H), 8.24 (s, 1H) 5 protons not seen

Example 34 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-piperidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was made according to the route outlined in Scheme 3.The title compound was prepared from Example 1.

Step 1: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-formyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (100 mg, 0.25 mmol),4-formylphenylboronic acid (41.6 mg, 0.28 mmol), K₂CO₃ (103.7 mg, 0.75mmol) and Pd(dppf)Cl₂ (18.3 mg, 0.025 mmol) were combined in THF/H₂O(2.1 mL: 0.23 mL) and thoroughly degassed. The reaction mixture washeated at 120° C. for 1 hour under microwave irradiation. The reactionwas diluted with EtOAc, washed with H₂O, the aqueous was extracted againwith EtOAc and the combined organics were washed with saturated aqueoussodium chloride, dried (MgSO₄) and solvent removed in vacuo to afford abrown gum. This crude material was purified by automated columnchromatography, eluting with DCM to 7% MeOH/DCM (gradient). Fractionsfound to contain pure material were combined and solvent removed invacuo to afford the desired product as a pale yellow solid, 76.5 mg,71.9%.

Step 2: Preparation of Title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid[5-(4-piperidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-formyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide (76.5 mg, 0.18mmol) and piperidine (0.05 mL, 0.54 mmol) were stirred in THF (6 mL) atRT for 10 minutes. NaBH(OAc)₃ (190.8 mg, 0.90 mmol) was added and thereaction was stirred at RT 18 hours. The reaction mixture was quenchedby the addition of saturated aqueous NaHCO₃ and extracted with EtOAc(2×30 mL). The combined organic extracts were washed with saturatedaqueous sodium chloride, dried (MgSO₄) and concentrated in vacuo toafford a yellow gum.

Crude material was purified by automated column chromatography, elutingwith DCM to 16% MeOH/DCM (gradient). Fractions found to contain productwere combined and solvent removed in vacuo to afford the title compoundas a cream solid, 35.2 mg, 39.5%.

LC/MS: RT=1.90 Min (270 nm), m/z=491.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.39-1.41 (m, 2H), 1.48-1.52 (m, 4H), 2.32-2.35 (m,4H), 3.47 (s, 2H), 5.41 (s, 2H), 7.29-7.34 (m, 3H), 7.36-7.41 (m, 4H),7.64 (d, 2H), 7.82 (d, 1H), 8.10 (s, 1H), 8.47 (s, 1H), 8.49 (d, 1H),8.53 (d, 1H), 9.90 (s, 1H), 11.49 (d, 1H)

Example 35 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 34, Step 1 andthe following change to the described protocol for Step 2.

Step 2: 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-formyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide (50 mg, 0.12mmol) was dissolved in DMF (5 mL) at rtp. To this was added(2-methoxy-ethyl)-methyl-amine (158.6 mg, 1.78 mmol) and AcOH (0.050mL). The solution was then evacuated and backfilled with N2. 10%Palladium on charcoal (25.3 mg) was added then the reaction wasevacuated and backfilled with N2 once more, then evacuated andbackfilled with H₂. The reaction was then stirred under H₂ at 45° C. for16 hours. To the reaction mixture was added a further 15eq of amine and50 uL of AcOH and the reaction was heated at 45° C. under H₂ for afurther 24 hours. The catalyst was separated via filtration and thefilter cake washed with a further portion of DMF (1 mL). The filtratewas concentrated in vacuo and the residue purified by preparative HPLCfirst at pH4 and then pH9 to furnish the title compound, 7.9 mg, 13.5%as a brown solid.

LC/MS: RT=1.91 Min (254 nm), m/z=495 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 2.19 (s, 3H), 2.54 (t, 2H), 3.24 (s, 3H), 3.47 (t,2H), 3.55 (s, 2H), 5.41 (s, 2H), 7.27-7.35 (m, 7H), 7.66 (m, 2H), 7.82(d, 1H), 8.10 (d, 1H), 8.47 (s, 1H), 8.50 (d, 1H), 8.53 (d, 1H), 9.91(s, 1H), 11.49 (br d, 1H)

Example 36 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 34, substitutingpyrrolidine (25.6 mg, 0.36 mmol) for piperidine in Step 2. It wasisolated as a formate salt, 21 mg, 37.1%, following purification bypreparative HPLC at pH 4.

LC/MS: RT=1.87 Min (270 nm), m/z=477 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.69-1.76 (m, 4H), 5.41 (s, 2H), 7.28-7.45 (m, 7H),7.65-7.68 (m, 2H), 7.82 (d, 1H), 8.10 (s, 1H), 8.23 (s, 1H), 8.47 (s,1H), 8.49-8.51 (m, 1H), 8.53-8.55 (m, 1H), 9.92 (s, 1H), 11.49 (br d,1H) 6 protons not seen

Example 37 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(4-fluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 34, substituting4-fluoro-piperidine hydrochloride (99.4 mg, 0.71 mmol) for piperidine inStep 2. It was isolated as a white solid, 21 mg, 34%, followingpurification by automated column chromatography eluting with DCM to 8%MeOH/DCM (gradient) and trituration with acetonitrile.

LC/MS: RT=1.93 Min (270 nm), m/z=509 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.67-1.92 (m, 4H), 2.32 (m, 2H), 2.52 (m, 2H), 3.52(s, 2H), 4.61-4.76 (m, 1H), 5.41 (s, 2H), 7.29-7.42 (m, 7H), 7.66 (m,2H), 7.82 (s, 1H), 8.10 (s, 1H), 8.47-8.53 (m, 3H), 9.90 (s, 1H), 11.49(br s, 1H)

Example 38 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-dimethylaminomethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 35, substitutingdimethylamine solution, 2.0M in THF (1.07 mL, 2.14 mmol) for(2-methoxy-ethyl)-methyl-amine in Step 2. It was isolated as a yellowsolid, containing 0.5 equivalents of formate salt, 4.4 mg, 13.7%,following purification by preparative HPLC at pH 9.

LC/MS: RT=1.84 Min (254 nm), m/z=451 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 2.18 (s, 6H), 3.45 (s, 2H), 5.41 (s, 2H), 7.28-7.42(m, 7H), 7.67 (m, 2H), 7.82 (d, 1H), 8.10 (d, 1H), 8.22 (s, 0.5Hformate), 8.47 (s, 1H), 8.50 (d, 1H), 8.54 (d, 1H), 9.91 (s, 1H), 11.49(br d, 1H)

Example 39 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(3-fluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 34, substituting3-fluoro-piperidine hydrochloride (99.4 mg, 0.71 mmol) for piperidine inStep 2. It was isolated as a white solid, 17 mg, 28%, followingpurification by automated column chromatography eluting with DCM to 10%MeOH/DCM (gradient) and trituration with acetonitrile.

LC/MS: RT=1.91 Min (270 nm), m/z=509 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.44-1.56 (m, 2H), 1.68-1.87 (m, 2H), 2.24-2.44 (m,2H), 2.66-2.75 (m, 2H), 3.56 (s, 2H), 4.55-4.71 (m, 1H), 5.41 (s, 2H),7.29-7.42 (m, 7H), 7.66 (m, 2H), 7.82 (s, 1H), 8.10 (s, 1H), 8.47-8.53(m, 3H), 9.90 (s, 1H), 11.49 (br s, 1H)

Example 40 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-methylaminomethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 35, substitutingmethylamine solution, 2.0M in THF (1.07 mL, 2.14 mmol) for(2-methoxy-ethyl)-methyl-amine in Step 2. It was isolated as a pinksolid, 4 mg, 12.9%, following purification by preparative HPLC at pH 4.

LC/MS: RT=1.83 Min (254 nm), m/z=437 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 2.37 (s, 3H), 3.83 (s, 2H), 5.41 (s, 2H), 7.28-7.41(m, 5H), 7.48 (m, 2H), 7.69 (m, 2H), 7.82 (d, 1H), 8.10 (s, 1H), 8.36(s, 1H), 8.49 (s, 1H), 8.52 (d, 1H), 8.55 (d, 1H), 9.96 (s, 1H), 11.52(br d, 1H)

Example 41 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-morpholin-4-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 34, substitutingmorpholine (51.7 mg, 0.59 mmol) for piperidine in Step 2. It wasisolated as an off white solid, 28.4 mg, 48.6%, following purificationby column chromatography eluting with DCM-5% MeOH/DCM (gradient) andpreparative HPLC at pH4.

LC/MS: RT=1.86 Min (254 nm), m/z=493 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 2.38 (m, 4H), 3.51 (s, 2H), 3.59 (m, 4H), 5.41 (s,2H), 7.28-7.45 (m, 7H), 7.67 (m, 2H), 7.81 (d, 1H), 8.09 (s, 1H), 8.47(s, 1H), 8.49 (d, 1H), 8.53 (d, 1H), 9.91 (s, 1H), 11.49 (br d, 1H)

Example 42 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(3,3-difluoro-Pyrrolidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 34, substituting3,3-difluoropyrrolidine hydrochloride (102.2 mg, 0.71 mmol) forpiperidine in Step 2. It was isolated as a white solid, 22 mg, 36.2%,following purification by automated column chromatography eluting withDCM to 10% MeOH/DCM (gradient) and trituration with acetonitrile.

LC/MS: RT=2.17 Min (270 nm), m/z=513 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 2.26 (m, 2H), 2.72 (t, 2H), 2.88 (t, 2H), 3.67 (s,2H), 5.41 (s, 2H), 7.29-7.44 (m, 7H), 7.69 (m, 2H), 7.82 (s, 1H), 8.10(s, 1H), 8.47-8.53 (m, 3H), 9.90 (s, 1H), 11.50 (br s, 1H)

Example 43 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-dimethylaminomethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 4. The title compound was prepared from Example 1.

Step 1: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

To a solution of 1-benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide 93.5 g, 8.83 mmol) in DCM(75 ml) was added tetrabutylammonium hydrogen sulphate 0.45 g, 1.32mmol), aqueous sodium hydroxide solution (50%, w/v, 7 mL) and tosylchloride (2.02 g, 10.6 mmol). The reaction mixture was stirred at RT for4 hours and then diluted with DCM. It was washed with aqueous 1M HCl,saturated aqueous bicarbonate, saturated aqueous sodium chloride, dried(MgSO₄) and concentrated in vacuo. The residue was purified viaautomated column chromatography eluting with iso-hexane to 75%EtOAc/iso-hexane (gradient). This furnished the desired compound as abrown foam, 3.51 g, 61.4%.

Step 2: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-formyl-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(595 mg, 1.08 mmol), 3-formylphenylboronic acid (195 mg, 1.3 mmol),K₂CO₃ (448 mg, 3.24 mmol) and Pd(dppf)Cl₂ (39.6 mg, 0.05 mmol) werecombined in THF/H₂O (10 mL/1 mL) and thoroughly degassed. The reactionmixture was heated at 120° C. for 1 hour under microwave irradiation.The reaction was diluted with EtOAc, washed with H₂O, the aqueous wasextracted again with EtOAc and the combined organics were washed withsaturated aqueous sodium chloride, dried (MgSO₄) and solvent removed invacuo to afford a brown gum. This crude material was purified byautomated column chromatography, eluting with iso-hexane to 50%EtOAc/iso-hexane to EtOAc (gradient). Fractions found to contain purematerial were combined and solvent removed in vacuo to afford thedesired product as a yellow solid, 420 mg, 67.5%.

Step 3: Preparation of 1-benzyl-1H-pyrazole-4-carboxylic acid[5-(3-dimethylaminomethyl-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

To a solution of 1-benzyl-1H-pyrazole-4-carboxylic acid[5-(3-formyl-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(100 mg, 0.17 mmol) in MeOH (1 mL) was added 4 A molecular sievesfollowed by dimethylamine, 2.0M solution in THF (4 mL, 8 mmol) and thereaction stirred for 3 hours at RT. Sodium triacetoxyborohydride (72.1mg, 0.34 mmol) was added and the reaction stirred 18 hours at RT. Theinorganic material was separated via filtration and the filtrate wasdiluted with DCM. The solution was washed with aqueous saturated sodiumbicarbonate solution, dried (MgSO₄) and concentrated in vacuo. Theresidue was purified using automated column chromatography eluting withDCM to 10% MeOH/DCM. Fractions containing pure compound were combinedand concentrated in vacuo to give the desired compound as a colourlessglass, 61 mg, 58.0%.

Step 4: Preparation of Title compound: 1-benzyl-1H-pyrazole-4-carboxylicacid[5-(3-dimethylaminomethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-dimethylaminomethyl-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(61 mg, 0.10 mmol) was dissolved in a mixture of THF (2 mL) and MeOH (1mL) and potassium hydroxide (26.6 mg, 0.474 mmol) in the minimum volumeof H₂O was added. After stirring at RT for 18 hours the reaction mixturewas diluted with H₂O and stirring continued. After 1 hour the solidswere separated via filtration and the filter cake was washed with H₂Oprior to drying in vacuo at 40° C. This furnished the title compound asa yellow solid, 15 mg, 33.2%.

LC/MS: RT=0.99 Min (230 nm), m/z=451 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 2.18 (s, 6H), 3.47 (s, 2H), 5.42 (s, 2H), 7.25-7.46(m, 7H), 7.58-7.63 (m, 2H), 7.84 (s, 1H), 8.10 (s, 1H), 8.47 (s, 1H),8.50-8.53 (m, 2H), 9.95 (br s, 1H), 11.50 (br s, 1H)

Example 44 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3-fluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 43, substituting3-fluoropiperidine hydrochloride (47.5 mg, 0.34 mmol) for piperidine inStep 3. It was isolated as a yellow powder, 11.7 mg, 18.1%, followingpurification by preparative HPLC at pH9.

LC/MS: RT=1.04 Min (230 nm), m/z=509 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.40-1.60 (m, 2H), 1.67-1.90 (m, 2H), 2.24-2.32 (m,1H), 2.36-2.48 (m, 2H), 2.66-2.76 (m, 1H), 3.60 (s, 2H), 4.54-4.74 (m,1H), 5.42 (s, 2H), 7.28-7.40 (m, 6H), 7.45 (dd, 1H), 7.58-7.62 (m, 2H),7.84 (d, 1H), 8.10 (s, 1H), 8.47 (s, 1H), 8.50 (d, 1H), 8.52 (d, 1H),),9.96 (s, 1H), 11.51 (br d, 1H)

Example 45 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3,3-difluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 43, substituting3,3-difluoropiperidine hydrochloride (124 mg, 0.79 mmol) for piperidineand sodium cyanoborohydride (13.1 mg, 0.21 mmol) for sodiumtriacetoxyborohydride in Step 3.

Step 4: Preparation of Title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid{5-[3-(3,3-difluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-[3-(3,3-difluoro-piperidin-1-ylmethyl)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(100 mg, 0.147 mmol), potassium carbonate (138 mg, 1 mmol) and MeOH (4mL) were combined in a microwave vial and heated under microwaveirradiation at 100° C. for 30 minutes. The reaction mixture was dilutedwith H₂O and extracted with a mixture of DCM/IPA (3:1). The organicswere washed with saturated aqueous sodium chloride, dried (MgSO4) andconcentrated in vacuo. The residue was taken up in the minimum amount ofMeOH and then Et₂O was added until the solution started to go cloudy.This was left to stand for 1 hour then the crystals were filtered offand dried in vacuo at 40° C. to furnish the title compound as yellowcrystals, 30.3 mg, 38.6%.

LC/MS: RT=1.17 Min (230 nm), m/z=527 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.62-1.71 (m, 2H), 1.80-1.95 (m, 2H), 2.42-2.48 (m,2H), 2.61-2.70 (m, 2H), 3.67 (s, 2H), 5.41 (s, 2H), 7.28-7.40 (m, 6H),7.47 (dd, 1H), 7.59-7.63 (m, 2H), 7.83 (d, 1H), 8.10 (s, 1H), 8.47 (s,1H), 8.49 (d, 1H), 8.52 (d, 1H), 9.94 (s, 1H), 11.52 (br d, 1H)

Example 46 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-azetidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 45, substitutingazetidine (38.7 mg, 0.68 mmol) for piperidine in Step 3. In Step 4 theproduct precipitated after diluting with H₂O and was collected viafiltration, washed with H₂O, Et₂O and dried in vacuo at 40° C. tofurnish the title compound as an off white solid, 26.7 mg, 25.6%.

LC/MS: RT=1.00 Min (230 nm), m/z=463.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.94-2.02 (m, 2H), 3.12-3.18 (m, 4H), 3.60 (s, 2H),5.42 (s, 2H), 7.22-7.46 (m, 7H), 7.54-7.60 (m, 2H), 7.83 (s, 1H), 8.10(s, 1H), 8.46-8.53 (m, 3H), 9.8-10.2 (br s, 1H), 11-12 (br s, 1H)

Example 47 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3,3-difluoro-azetidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 45, substituting3,3-difluoroazetidine hydrochloride (114 mg, 0.88 mmol) for piperidineand sodium cyanoborohydride (13.1 mg, 0.21 mmol) for sodiumtriacetoxyborohydride in Step 3. In Step 4 the product precipitatedafter diluting with H₂O and was collected via filtration, washed withH₂O, Et₂O and dried in vacuo at 40° C. to furnish the title compound asa cream powder, 23.4 mg, 38.8%.

LC/MS: RT=1.15 Min (230 nm), m/z=499.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 3.64 (t, 4H), 3.81 (s, 2H), 5.42 (s, 2H), 7.28-7.41(m, 6H), 7.45 (dd, 1H), 7.59-7.65 (m, 2H), 7.84 (s, 1H), 8.10 (s, 1H),8.47 (s, 1H), 8.50 (d, 1H), 8.53 (d, 1H), 9.95 (br s, 1H), 11.51 (br s,1H)

Example 48 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 43, substituting5-formyl-2-thiopheneboronic acid 67.1 mg, 0.43 mmol) for3-formylphenylboronic acid, 2M aqueous sodium carbonate 76.3 mg, 0.72mmol) for K₂CO₃, tetrakis (19.6 mg, 0.017 mmol) for Pd(dppf)Cl₂ and1,4-dioxane/THF (4 mL:2 mL) for THF/H₂O (10:1) in Step 2. The reactionmixture was heated at 150° C. for 2 hours under microwave irradiation.The reaction was diluted with 3:1 DCM/IPA, washed with saturated aqueoussodium chloride, dried (MgSO₄) and concentrated in vacuo. The residuewas dissolved in the minimum amount of DCM and Et₂O was added toprecipitate the desired, deprotected, Suzuki product,1-benzyl-1H-pyrazole-4-carboxylic acid[5-(5-formyl-thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide, 68mgs, 43.8%. In Step 3 pyrrolidine (45.3 mg, 0.64 mmol) was substitutedfor piperidine and sodium cyanoborohydride (15 mg, 0.24 mmol) for sodiumtriacetoxyborohydride. The title compound was isolated as a white solid,5 mg, 6.5%, following purification by automated column chromatographyeluting with DCM to 20% MeOH/DCM (gradient), preparative HPLC at pH4 andfinally trituration with Et₂O.

LC/MS: RT=0.94 Min (230 nm), m/z=483 [M+H]. Total run time 1.9 min(super short pos), H P1200.

¹H NMR (d₆ DMSO): δ 1.68-1.76 (m, 4H), 3.79 (s, 2H), 5.42 (s, 2H), 6.95(d, 1H), 7.27-7.41 (m, 6H), 7.82 (s, 1H), 8.10 (s, 1H), 8.44 (d, 1H),8.48 (s, 1H), 8.55 (d, 1H), 9.94 (br s, 1H), 11.53 (br s, 1H) 4 protonsnot seen

Example 49 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-pyrrolidin-1-ylmethyl-thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 43, substituting5-formyl-3-thiopheneboronic acid (67.1 mg, 0.43 mmol) for3-formylphenylboronic acid, 2M aqueous sodium carbonate (76.3 mg, 0.72mmol) for K₂CO₃, tetrakis (19.6 mg, 0.017 mmol) for Pd(dppf)Cl₂ and1,4-dioxane (4 mL) for THF/H₂O (10:1) in Step 2. The reaction mixturewas heated at 150° C. for 20 minutes under microwave irradiation. Thereaction was diluted with DCM washed with saturated aqueous sodiumchloride, dried (MgSO₄) and concentrated in vacuo. The residue wasdissolved in the minimum amount of DCM and Et₂O was added to precipitatethe desired Suzuki product, 142 mgs, 64.9% as a brown powder. In Step 3pyrrolidine (34.2 mg, 0.48 mmol) was substituted for piperidine andsodium cyanoborohydride (11.3 mg, 0.18 mmol) for sodiumtriacetoxyborohydride. In Step 4 potassium carbonate (83.2 mg, 0.6 mmol)and MeOH (4 mL) were combined in a microwave vial and heated undermicrowave irradiation at 100° C. for 30 minutes. The reaction mixturewas diluted with H₂O and the precipitate was collected via filtration,washed with H₂O, Et₂O and dried in vacuo at 40° C. to furnish the titlecompound as a cream powder, 12.8 mg, 22%.

LC/MS: RT=0.94 Min (230 nm), m/z=483 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.68-1.76 (m, 4H), 3.82 (s, 2H), 5.42 (s, 2H),7.28-7.42 (m, 6H), 7.68 (d, 1H), 7.78 (s, 1H), 8.10 (s, 1H), 8.46 (d,1H), 8.48 (s, 1H), 8.59 (d, 1H), 9.83 (br s, 1H), 11-12 (br s, 1H) 4protons not seen

Example 50 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3,3-difluoro-azetidin-1-ylmethyl)-thiophen-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 49, substituting3,3-difluoro-azetidine hydrochloride (94.5 mg, 0.73 mmol) forpyrrolidine in Step 3.

It was isolated as a cream powder, 27.5 mg, 53.4%, following the sameprocedure described in Step 4.

LC/MS: RT=1.19 Min (230 nm), m/z=505 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 3.67 (t, 4H), 3.96 (s, 2H), 5.42 (s, 2H), 7.28-7.41(m, 5H), 7.44-7.46 (m, 1H), 7.72 (d, 1H), 7.78 (d, 1H), 8.10 (d, 1H),8.45 (d, 1H), 8.47 (s, 1H), 8.59 (d, 1H), 9.88 (br s, 1H), 11.47 (br d,1H)

Example 51 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 43, substitutingpyrrolidine (30 mg, 0.45 mmol) for dimethylamine, 2.0M solution in THFin Step 3. In Step 4 potassium carbonate (71.9 mg, 0.52 mmol) and MeOH(3 mL) were combined in a microwave vial and heated under microwaveirradiation at 100° C. for 30 minutes. The reaction mixture wasconcentrated to half volume in vacuo. H₂O was added to the residue andthe precipitate was collected via filtration, washed with H₂O, Et₂O anddried in vacuo at 40° C. to furnish the title compound as a creampowder, 38 mg, 76.8%.

LC/MS: RT=1.04 Min (230 nm), m/z=477 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.66-1.74 (m, 4H), 2.42-2.50 (m, 4H), 3.65 (s, 2H),5.42 (s, 2H), 7.28-7.45 (m, 7H), 7.56-7.64 (m, 2H), 7.83 (s, 1H), 8.10(s, 1H), 8.47 (s, 1H), 8.49-8.52 (m, 2H), 9.8-10.12 (br s, 1H), 11.12(br s, 1H)

Example 52 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2.

The title compound was prepared as described in Example 6, substitutingN-fluorobis(phenylsulphonyl)amine (1.08 g, 3.42 mmol) for carbontetrabromide in Step 3, and the desired intermediate was isolated as awhite solid, 134 mg, 63.4%. The crude material from Step 8 was purifiedby automated column chromatography, eluting with DCM-16% MeOH/DCM(gradient) and then preparative HPLC at pH 4. The title compound wasisolated as a white solid, 34.3 mg, 46.6%.

LC/MS: RT=1.70 Min (270 nm), m/z=434.5 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.33-1.38 (m, 2H), 1.60-1.63 (m, 1H), 1.74-1.76 (m,1H), 2.98-3.14 (m, 4H), 3.46-3.48 (m, 1H), 5.41 (s, 2H), 7.24-7.26 (m,2H), 7.31-7.39 (m, 3H), 7.52 (s, 1H), 8.07 (s, 1H), 8.09 (d, 1H), 8.48(s, 1H), 9.70 (s, 1H), 11.70 (br s, 1H) 2 protons not seen

Example 53 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 3. The title compound was prepared from1-benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide, the product ofStep 7 in Example 6.

Step 1: Preparation of((R)-1-{3-[(1-Benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester

1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (0.445 g, 1.07mmol), (R)-piperidin-3-yl-carbamic acid tert-butyl ester (1.08 g, 5.37mmol) and n-butanol (15 mL) were combined in a microwave vial. Thecontents were heated at 160° C. for 6 hours under microwave irradiationand then the reaction mixture was diluted with EtOAc. The solution waswashed with H₂O, saturated aqueous sodium chloride, dried (MgSO₄) andconcentrated in vacuo to afford a brown gum. This crude material waspurified by automated column chromatography, eluting with iso-hexane 50%EtOAc/iso-hexane-EtOAc (gradient). Fractions found to contain pureproduct were combined and concentrated in vacuo to afford the desiredcompound as a yellow powder, 443.2 mg, 69.4%.

Step 2: Preparation of Title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid[4-((R)-3-amino-piperidin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

Phenylboronic acid (17.9 mg, 0.15 mmol),((R)-1-{3-[(1-Benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (48.4 mg, 0.08 mmol), K₂CO₃ (34.6 mg, 0.25 mmol),

Pd(dppf)Cl₂ (8.0 mg, 0.01 mmol) and THF/H₂O (4.5 mL: 0.5 mL) werecombined in a microwave vial and thoroughly degassed. The reactionmixture was heated at 100° C. for 1 hour under microwave irradiation andthen it was diluted with EtOAc. The organic layer was separated and theaqueous extracted with another portion of EtOAc. The combined organicswere washed with H₂O, saturated aqueous sodium chloride, dried (MgSO₄)and solvent removed in vacuo to afford a brown gum. This material wastaken up in DCM (10 mL) and cooled in an ice bath followed by drop wiseaddition of TFA (0.03 mL, 0.4 mmol). Stirring was continued for 4 hoursat RT and the solvents removed in vacuo. The crude material was purifiedby automated column chromatography, eluting with DCM-15% MeOH/DCM.Fractions found to contain pure material were combined and solventremoved in vacuo to afford the title compound as a solid, 22 mg, 55%.

LC/MS: RT=1.82 Min (270 nm), m/z=492 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ□ 1.35-1.45 (m, 2H), 1.56-1.67 (m, 1H), 2.25-2.37 (m,1H), 2.76-3.04 (m, 3H), 3.13-3.22 (m, 1H), 5.40 (s, 2H), 7.18-7.82 (m,11H), 7.89 (br s, 1H), 8.05 (s, 1H), 8.42 (s, 1H), 9.53 (s, 1H), 11.74(s, 1H)

Example 54 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared from((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester, the product of Step 1, Example 53.

((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (21 mg, 0.04 mmol), dicyanozinc (7.5 mg, 0.06mmol), Pd(PPh₃)₄ (6.1 mg, 0.01 mmol) and DMF (5 mL) were combined in amicrowave vial and degassed. The contents were heated under microwaveirradiation at 120° C. for 1 hour. A further portion of dicyano zinc(2.1 mg, 0.018 mmol) and Pd(PPh₃)₄ (2.0 mg) were added and degassed. Thecontents were heated under microwave irradiation at 120° C. for 2 hours.The reaction mixture was partitioned between EtOAc and H₂O, then theorganic layer was separated and the aqueous extracted with anotherportion of EtOAc. The combined organics were washed with H₂O, saturatedaqueous sodium chloride, dried (MgSO₄) and solvent removed in vacuo toafford a brown gum. The crude product was purified by automated columnchromatography eluting with iso-hexane 50% EtOAc/iso-hexane-EtOAc(gradient). Fractions found to contain pure material were combined andsolvent removed in vacuo to afford((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester. This material was taken up in hydrochloric acidsolution, 1.25 M in MeOH (5 mL) and irradiated in a microwave for 1 hourat 80° C. The volatiles were removed in vacuo and the residue was takenup in the minimum volume of MeOH and loaded onto a SCX2 ion exchangecolumn that had been primed with MeOH. The column was washed with DCM,MeOH and the title compound was eluted using ammonia solution, 3.5M inMeOH. This solution was concentrated in vacuo to afford the titlecompound as a white solid, 3 mg, 19.3%.

LC/MS: RT=1.67 Min (270 nm), m/z=441 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₄ MeOH): δ 1.35-1.98 (m, 4H), 3.18-3.26 (m, 1H), 3.47-3.56 (m,1H), 3.84-3.90 (m, 1H), 5.41 (s, 2H), 7.24-7.40 (m, 5H), 7.43 (s, 1H),8.08 (s, 1H), 8.26 (s, 1H), 8.36 (s, 1H) 6 protons not seen

Example 55 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared according to the route outlined inScheme 5. The title compound was prepared from1-benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide,the product of Step 1, Example 43.

Step 1: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (408 mg, 1.85mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(850 mg, 1.54 mmol), K₂CO₃ (640 mg, 4.63 mmol), Pd(dppf)Cl₂ (56.5 mg,0.077 mmol) and THF/H₂O (12 mL: 1.2 mL) were combined in a microwavevial and thoroughly degassed. The reaction mixture was heated at 120° C.for 1 hour under microwave irradiation and then it was diluted withEtOAc. The organic layer was separated and the aqueous extracted withanother portion of EtOAc. The combined organics were washed with H₂O,saturated aqueous sodium chloride, dried (MgSO₄) and solvent removed invacuo. The crude product was purified by automated column chromatographyeluting with iso-hexane to 50% EtOAc/iso-hexane to EtOAc (gradient).Fractions found to contain pure material were combined and solventremoved in vacuo to afford the desired compound as a yellow glass, 518mg, 59.5%.

Step 2: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-hydroxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(80 mg, 0.14 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (37.0mg, 0.2 mmol) were combined in anhydrous DMF (3 mL) and to this wasadded Cs₂CO₃ (138.7 mg, 0.43 mmol). The reaction was heated at 60° C.for 3 hours and then allowed to cool to RT. The reaction mixture wasdiluted with H₂O and extracted with DCM (×2). The combined organicphases were washed saturated aqueous sodium chloride (×4), dried (MgSO₄)and concentrated in vacuo. The crude material was purified via automatedcolumn chromatography eluting with DCM to 10% MeOH/DCM (gradient) tofurnish the desired compound as a yellow glass, 50 mg, 52.1%.

Step 3: Preparation of title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid{5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(50 mg, 0.07 mmol) potassium carbonate (51.1 mg, 037 mmol) and MeOH (4mL) were combined in a microwave vial and heated under microwaveirradiation at 100° C. for 30 minutes. The reaction mixture was reducedto half volume in vacuo and diluted with H₂O.

The mixture was stirred for 1 hour at RT and the precipitate wascollected via filtration, washed with H₂O, Et₂O and dried in vacuo at40° C. This afforded the title compound as a pale yellow powder, 20 mg,51.8%.

LC/MS: RT=1.02 Min (230 nm), m/z=523 [M+H]. Total run time 1.9 min(super short pos), H P1200.

¹H NMR (d₆ DMSO): δ 2.72 (t, 2H), 3.56-3.61 (m, 4H), 4.18 (t, 2H), 5.42(s, 2H), 6.92-6.96 (m, 1H), 7.24-7.42 (m, 8H), 7.83 (s, 1H), 8.10 (s,1H), 8.47 (s, 1H), 8.51 (d, 1H), 8.55 (d, 1H), 9.90 (br s, 1H),11.3-11.7 (br s, 1H) 4 protons not seen.

Example 56 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3-dimethylamino-2,2-dimethyl-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

Preparation of (3-chloro-2,2-dimethyl-propyl)-dimethyl-aminehydrochloride

To a solution of 3-dimethylamino-2,2-dimethyl-propan-1-ol (5 g, 38.1mmol) in toluene (100 mL) was added DMF (1 drop) followed by thionylchloride (5 g, 41.9 mmol) drop wise at RT. After addition the reactionwas heated at reflux for 3 hours and then allowed to cool to RT. Thesolvent was removed in vacuo and toluene (50 mL) was added and removedin vacuo. This process was repeated three more times. Toluene (50 mL)was added and the solids broken up by sonication for 10 minutes. Thesolid was collected via filtration, washed well with toluene, iso-hexaneand dried in vacuo. This afforded the desired compound as a light brownsolid, 6.68 g, 94%.

The title compound was prepared as described in Example 55, substituting(3-chloro-2,2-dimethyl-propyl)-dimethyl-amine hydrochloride (30.1 mg,0.16 mmol) for 4-(2-chloroethyl)morpholine hydrochloride in Step 2,except heating was conducted for 18 hours at 60° C. It was isolated as apale yellow powder, 6.5 mg, 33.7%, following the same proceduredescribed in Step 3.

LC/MS: RT=1.10 Min (230 nm), m/z=523.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 0.98 (s, 6H), 2.22 (s, 6H), 2.26 (s, 2H), 3.78 (s,2H), 5.42 (s, 2H), 6.92-6.96 (m, 1H), 7.22-7.42 (m, 8H), 7.85 (s, 1H),8.10 (s, 1H), 8.47 (s, 1H), 8.51-8.56 (m, 2H), 9.92 (br s, 1H), 11.50(br s, 1H)

Example 57 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3-morpholin-4-yl-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 55, substituting4-(3-chloropropyl)morpholine (31.9 mg, 0.195 mmol) for4-(2-chloroethyl)morpholine in Step 2, except heating was conducted for18 hours at 60° C. It was isolated as a powder, 8 mg, 20.2%, followingthe same procedure described in Step 3 and extra purification viapreparative HPLC at pH4.

LC/MS: RT=1.06 Min (230 nm), m/z=537.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.91 (quintet, 2H), 2.33-2.40 (m, 4H), 2.44 (t, 2H),3.53-3.60 (m, 4H), 4.10 (t, 2H), 5.42 (s, 2H) 6.90-6.96 (m, 1H),7.20-7.42 (m, 8H), 7.84 (s, 1H), 8.10 (s, 1H), 8.48 (s, 1H), 8.51-8.56(m, 2H), 9.92 (br s, 1H), 11.51 (br s, 1H)

Example 58 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 55, substituting3-bromomethyl-1-methyl-piperidine (40.7 mg, 0.21 mmol) for4-(2-chloroethyl)morpholine hydrochloride in Step 2, except heating wasconducted for 18 hours at 70° C. It was isolated as a white powder, 8.8mg, 38%, following the same procedure described in Step 3.

LC/MS: RT=1.01 Min (230 nm), m/z=521 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.03-1.14 (m, 1H), 1.44-1.56 (m, 1H), 1.60-1.68 (m,1H), 1.70-1.84 (m, 2H), 1.84-1.94 (m, 1H), 1.98-2.06 (m, 1H), 2.15 (s,3H), 2.59-2.66 (m, 1H), 2.80-2.86 (m, 1H), 3.88-3.98 (m, 2H), 5.42 (s,2H), 6.90-6.96 (m, 1H), 7.22-7.42 (m, 8H), 7.83 (s, 1H), 8.10 (s, 1H),8.48 (s, H), 8.53 (dd, 2H), 9.91 (br s, 1H), 11.5 (br s, 1H)

Example 59 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(oxetan-3-yloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 55, substituting3-iodo-oxetane (35.9 mg, 0.195 mmol) for 4-(2-chloroethyl)morpholinehydrochloride in Step 2, except heating was conducted for 18 hours at60° C. It was isolated as a beige powder, 4 mg, 10.9%, following thesame procedure described in Step 3, and extra purification via automatedcolumn chromatography eluting with DCM to 10% MeOH/DCM (gradient).

LC/MS: RT=1.17 Min (230 nm), m/z=466.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 4.59 (dd, 2H), 4.97 (dd, 2H), 5.37-5.43 (m, 3H)6.74-6.78 (m, 1H), 7.12-7.14 (m, 1H), 7.28-7.44 (m, 7H), 7.82 (d, 1H),8.10 (s, 1H), 8.47 (s, 1H), 8.51 (d, 1H), 8.54 (d, 1H), 9.90 (br s, 1H),11.52 (br d, 1H)

Example 60 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared according to the route outlined inScheme 6. The title compound was prepared from1-benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide,the product of Step 1 in Example 43.

Step 1: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(215 mg, 0.39 mmol), bis(pinacolato)diboron (218.2 mg, 0.86 mmol),sodium acetate (96.1 mg, 1.17 mmol) and DMF (2 mL) were combined in amicrowave vial. The contents were degassed by sparging with N₂ thenPd(dppf)Cl₂ (14.3 mg, 0.02 mmol) was added and the mixture heated undermicrowave irradiation at 140° C. for 1 hour. Bis(pinacolato)diboron(78.9 mg, 0.31 mmol) was added and the contents were degassed bysparging with N₂. Pd(dppf)Cl₂ (7.1 mg, 0.01 mmol) was added and thereaction was heated under microwave irradiation at 140° C. for 30minutes. The reaction mixture was diluted with DCM and washed withsaturated aqueous sodium chloride (×4), dried (MgSO₄) and solventremoved in vacuo. The crude product was purified by automated columnchromatography eluting with iso-hexane to 50% EtOAc/iso-hexane to EtOAc(gradient) to afford the desired compound as a yellow gum, 185 mg,79.3%.

Step 2: Preparation of 1-[2-(3-Bromo-phenoxy)-ethyl]-pyrrolidine

3-Bromophenol (5 g, 28.9 mmol), 1-(2-chloroethyl)pyrrolidinehydrochloride (5.9 g, 34.7 mmol) were stirred in DMF (100 mL). Cesiumcarbonate (18.83 g, 57.8 mmol) was added and the reaction was heated at100° C. for 4 hours. The reaction was cooled and the solvent removed invacuo. The residue was taken up in EtOAc, washed with H₂O, saturatedaqueous sodium chloride (×4), dried (MgSO₄) and concentrated in vacuo.The crude material was purified via flash chromatography eluting with50% EtOAc/iso-hexane and then 67% EtOAc/iso-hexane to afford the desiredcompound as a brown oil, 1.24 g, 15.9%.

Step 3: Preparation of 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared as described in Example 55, substituting1-benzyl-1H-pyrazole-4-carboxyl ic acid[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(72 mg, 0.12 mmol) for3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and1-[2-(3-bromo-phenoxy)-ethyl]-pyrrolidine 65.1 mg, 0.24 mmol) for1-benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide, inStep 1. The crude product was purified by automated columnchromatography eluting with DCM to 10% MeOH/DCM (gradient) to afford thedesired compound as a beige glass, 38 mg, 47.9%.

Step 4: Preparation of Title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid{5-[3-(2-pyrrolidi-1-yl-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared as described in Example 55, substituting1-benzyl-1H-pyrazole-4-carboxylic acid[5-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(38 mg, 0.058 mmol) for 1-benzyl-1H-pyrazole-4-carboxylic acid[5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide,in Step 3. Following the usual work up, and trituration of the solidobtained with acetonitrile, the title compound was isolated as a beigepowder, 8.6 mg, 29.5%.

LC/MS: RT=0.99 Min (230 nm), m/z=507 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.64-1.73 (m, 4H), 2.82 (t, 2H), 4.15 (t, 2H), 5.42(s, 2H), 6.92-6.96 (m, 1H), 7.24-7.42 (m, 8H), 7.83 (s, 1H), 8.10 (s,1H), 8.48 (s, 1H), 8.51 (d, 1H), 8.55 (d, 1H), 9.91 (br s, 1H),11.34-11.64 (br s, 1H) 4 protons not seen

Example 61 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((3R,4R)-3-amino-4-cyclopropyl-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 2. The title compound was prepared from the product of Step 7, inExample 6,1-benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide and((3R,4R)-4-cyclopropyl-piperidin-3-yl)-phosphoramidic acid diethylester.

Preparation of ((3R,4R)-4-Cyclopropyl-piperidin-3-yl)-phosphoramidicacid diethyl ester Step 1: Preparation of3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester

1,2,3,6-tetrahydropyridine (5.24 g, 63 mmol) was stirred in DCM (30 mL)and cooled to 0° C. Et₃N (9.6 g, 95 mmol) was added followed by benzylchloroformate (11.3 g, 66.2 mmol) drop wise. After addition the reactionwas stirred at 5° C. for 30 minutes and then at RT for 2 hours. Thereaction mixture was washed with saturated aqueous Na₂CO₃, dried (MgSO₄)and concentrated in vacuo. Crude material was purified by automatedcolumn chromatography, eluting with iso-Hexane to 10% EtOAc/iso-Hexane(gradient). Fractions found to contain product were combined and solventremoved in vacuo to afford the title compound as a colourless oil, 9.8g, 71.6%.

Step 2: Preparation of 7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylicacid benzyl ester

To a solution of 7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acidbenzyl ester (6.86 g, 31.6 mmol) in DCM (65 mL) at 0° C. was addedm-CPBA (8.28 g, 48 mmol) portion wise. After addition the reaction wasmaintained at 5° C. for 20 minutes and then at RT for 4 hours. Thereaction mixture was diluted with Et₂O (150 mL), washed with 1N NaOHsolution (2×50 mL), sat sodium thiosulphate solution (2×50 mL) andsaturated aqueous sodium chloride. The organics were dried (MgSO₄) andconcentrated in vacuo. Crude material was purified by automated columnchromatography, eluting with iso-hexane to 10% EtOAc/iso-Hexane(gradient). Fractions found to contain product were combined and solventremoved in vacuo to afford the desired compound as a colourless gum,5.88 g, 79.8%

Step 3: Preparation of 4-Azido-3-hydroxy-piperidine-1-carboxylic acidbenzyl ester and 3-azido-4-hydroxy-piperidine-1-carboxylic acid benzylester

7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (3.35g, 14.3 mmol) was dissolved in MeOH/H₂O 5:1 (48 mL) and ammoniumchloride (0.77 g, 14.3 mmol) was added followed by sodium azide (1.87 g,28.7 mmol). The reaction mixture was heated at 65° C. for 18 hours. TheMeOH was removed in vacuo and the residue diluted with H₂O (15 mL) andextracted with Et₂O (×2). The combined organics were washed withsaturated aqueous sodium chloride, dried (MgSO₄) and concentrated invacuo to give the desired mixture of regioisomers, 3.84 g, 96.9%, as acolourless oil. The mixture contained a 3:1 ratio (3:1) of4-azido-3-hydroxy-piperidine-1-carboxylic acid benzyl ester to3-azido-4-hydroxy-piperidine-1-carboxylic acid benzyl ester.

Step 4: Preparation of4-Azido-3-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid benzylester and 3-azido-4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acidbenzyl ester

4-Azido-3-hydroxy-piperidine-1-carboxylic acid benzyl ester and3-azido-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (3.84 g,13.9 mmol) were dissolved in DCM (18 mL) and pyridine (2.97 g, 37.53mmol) was added. The solution was cooled to 0° C. and p-toluenesulfonylchloride (5.56 g, 29.2 mmol) in DCM (7 mL) was added drop wise. Thereaction was allowed to stir at RT for 68 hours. Pyridine (1.96 g, 24.8mmol) and p-toluenesulfonyl chloride (1 g, 5.25 mmol) were added and thereaction was stirred at RT for 24 hrs. The reaction mixture wasconcentrated in vacuo to give a white solid that was dissolved in EtOAcand washed with saturated aqueous sodium chloride, dried (MgSO₄) andconcentrated in vacuo. The crude material was purified via automatedcolumn chromatography eluting with iso-hexane to 50% EtOAc/iso-hexane(gradient) to give the desired mixture of regioisomers, 5.62 g, 94%, asa colourless oil. The mixture contained a ratio (77:23) of4-azido-3-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid benzylester to 3-azido-4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acidbenzyl ester.

Step 5: Preparation of4-Amino-3-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid benzylester and 3-amino-4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acidbenzyl ester

Sodium borohydride (300 mg, 7.93 mmol) was added in portions to asolution of copper(II)sulphate pentahydrate (1.04 g, 4.15 mmol) in MeOH(20 mL) at 0° C. After 5 minutes a solution of4-azido-3-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid benzylester and 3-azido-4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acidbenzyl ester (3.57 g, 8.29 mmol) in MeOH (10 mL) was added drop wise,followed by sodium borohydride (600 mg, 15.86 mmol) in portions. Afteraddition stirring was continued at 0° C. for 1 hour. The reactionmixture was filtered through a plug of celite and concentrated in vacuo.The residue was taken up in DCM then washed with H₂O, saturated aqueousammonium chloride, saturated aqueous sodium chloride, dried (MgSO₄) andconcentrated in vacuo. The desired mixture of regioisomers was obtainedas a colourless oil, 2.77 g, 83.3%.

Step 6 Preparation of4-(Diethoxy-phosphorylamino)-3-(toluene-4-sulfonyloxy)-piperidine-1-carboxylicacid benzyl ester and3-(diethoxy-phosphorylamino)-4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylicacid benzyl ester

To a solution of4-amino-3-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid benzylester and 3-amino-4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acidbenzyl ester 2.77 g, 6.84 mmol) in DCM (22 mL) was added triethylamine(1.38 g, 13.68 mmol) and the solution cooled to 0° C. Diethylchlorophosphate (1.3 g, 7.52 mmol) was added and the mixture allowed toattain RT over 30 minutes. Diethyl chlorophosphate (0.24 g 1.38 mmol)was added and stirred for 30 minutes at RT. The reaction was dilutedwith H₂O and the organics separated, washed with saturated aqueoussodium chloride, dried (MgSO₄) and concentrated in vacuo. EtOAc wasadded to the residue and the crystals formed were collected viafiltration and dried in vacuo to afford the desired compound, 0.604 g,16.4%. The filtrate was concentrated in vacuo and the residue purifiedvia automated column chromatography eluting with EtOAc to afford more ofthe desired compound, 2.76 g, 74.8%, as a colorless oil.

Step 7: Preparation of7-(Diethoxy-phosphoryl)-3,7-diaza-bicyclo[4.1.0]heptane-3-carboxylicacid benzyl ester

To a solution of4-(diethoxy-phosphorylamino)-3-(toluene-4-sulfonyloxy)-piperidine-1-carboxylicacid benzyl ester and3-(diethoxy-phosphorylamino)-4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylicacid benzyl ester (2.6 g, 4.81 mmol) in THF (25 mL) at 0° C. was addedsodium hydride, 60% dispersion in mineral oil, (288.6 mg, 7.21 mmol) inportions. The reaction was stirred for 30 minutes then diluted with H₂O.The mixture was extracted with EtOAc (×2) and the combined organics werewashed with saturated aqueous sodium chloride, dried (MgSO₄) andconcentrated in vacuo. The residue was purified via automated columnchromatography eluting with EtOAc to give the desired compound as acolourless oil, 1.34 g, 76.5%.

Step 8: Preparation of(3R,4R)-4-Cyclopropyl-3-(diethoxy-phosphorylamino)-piperidine-1-carboxylicacid benzyl ester

To a suspension of copper(I)iodide (38.8 mg, 0.2 mmol) in THF (10 mL) at−30° C. was added cyclopropylmagnesium bromide, 0.5M in THF (16.3 mL,8.15 mmol) drop wise. This was stirred for 15 minutes, then7-(diethoxy-phosphoryl)-3,7-diaza-bicyclo[4.1.0]heptane-3-carboxylicacid benzyl ester (750 mg, 2.04 mmol) in THF (5 mL) was added drop wiseat −30° C. The reaction was warmed to RT over 2 hours, and diluted withEtOAc and H₂O and the resultant emulsion filtered through celite. Thefiltrate was transferred to a separating funnel. The organics wereseparated and the aqueous extracted with EtOAc. The combined organicswere washed with saturated aqueous sodium chloride, dried (MgSO₄) andconcentrated in vacuo. The resultant yellow oil was purified viaautomated column chromatography eluting with EtOAc, to afford thedesired compound as a gum, 321 mg, 38.4%, that solidified on standing.

Step 9: Preparation of((3R,4R)-4-Cyclopropyl-piperidin-3-yl)-phosphoramidic acid diethyl ester

(3R,4R)-4-Cyclopropyl-3-(diethoxy-phosphorylamino)-piperidine-1-carboxylicacid benzyl ester (321 mg, 0.78 mmol) was dissolved in MeOH (5 mL) andpalladium on charcoal, 10% (20 mg) was added under a stream of N₂. Thiswas then evacuated and back filled with nitrogen three times, beforefinally evacuating and connecting to a hydrogen atmosphere. The reactionmixture was shaken under hydrogen for 5 hours. The reaction wasevacuated and back filled with nitrogen three times. The mixture wasfiltered through a pad of celite and the filtrate concentrated in vacuoto give the desired amine,((3R,4R)-4-cyclopropyl-piperidin-3-yl)-phosphoramidic acid diethylester, as a colourless oil, 232 mg.

Preparation of title compound: 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((3R,4R)-3-amino-4-cyclopropyl-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (90 mg, 0.22mmol), ((3R,4R)-4-cyclopropyl-piperidin-3-yl)-phosphoramidic aciddiethyl ester (230 mg, 0.83 mmol) and 1-butanol (5 mL) were combined ina sealed tube and heated at 3140-ES-085 at 160° C. for 60 hours. Thereaction mixture was concentrated in vacuo and the residue was purifiedvia automated column chromatography eluting with DCM to 25% MeOH/DCM(gradient). The material obtained was further purified by preparativeHPLC at pH4. The material obtained was taken up in DCM/IPA (3:1), washedwith saturated aqueous sodium hydrogen bicarbonate, dried (MgSO₄) andconcentrated in vacuo. The residue was dried in vacuo at 40° C. o/n toafford the desired title compound as a golden brown powder, 3.3 mg,2.84%.

LC/MS: RT=1.03 Min (230 nm), m/z=534 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 0.16-0.07 (m, 1H), 0.15-0.25 (m, 2H), 0.30-0.46 (m,3H), 1.31-1.44 (m, 1H), 1.64-1.76 (m, 1H), 2.71-2.81 (m, 1H), 2.92-3.03(m, 1H), 5.40 (s, 2H), 7.20-7.38 (m, 5H), 7.62 (s, 1H), 8.04 (s, 1H),8.18 (s, 1H), 8.46 (s, 1H), 9.63 (br s, 1H), 11.56-11.94 (br s, 1H) 5protons not seen

Example 62 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared by an analogous route to the oneoutlined in Scheme 4.

The title compound was prepared as described in Example 43, substituting2-fluoro-4-formyl boronic acid (109 mg, 0.65 mmol) for3-formylphenylboronic acid, saturated aqueous sodium hydrogen carbonate(2 mL) for K₂CO₃ and MeCN (4 mL) for THF/H₂O in Step 2. The reaction washeated at 130° C. for 2 hours under microwave irradiation. The reactionwas diluted with DCM, washed with H₂O, the aqueous was extracted againwith DCM and the combined organics were washed with saturated aqueoussodium chloride, dried (MgSO₄) and solvent removed in vacuo to afford abrown gum. This crude material was purified by automated columnchromatography, eluting with iso-hexane to 90% EtOAc/iso-hexane EtOAc(gradient). Fractions found to contain pure material were combined andsolvent removed in vacuo to afford the desired Suzuki product as ayellow glass, 108 mg, 50%.

In Step 3, pyrrolidine 925.2 mg, 0.35 mmol) was substituted fordimethylamine, 2.0M solution in THF and sodium cyanoborohydride (16.7mg, 0.27 mmol) was substituted for sodium triacetoxyborohydride.

The title compound was isolated as a white powder, 16.6 mg, 68.1%,following the usual protocol for deprotection of the tosyl group.

LC/MS: RT=1.00 Min (230 nm), m/z=495 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.69-1.75 (m, 4H), 2.45-2.49 (m, 4H), 3.64 (s, 2H),5.45 (s, 2H), 7.24-7.40 (m, 7H), 7.59-7.55 (m, 1H), 7.83 (s, 1H), 8.08(s, 1H), 8.37-8.39 (m, 1H), 8.40-8.42 (m, 1H), 8.46 (br s, 1H), 9.93 (brs, 1H), 11.56 (br s, 1H)

Example 63 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-pyrrolidin-1-yl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 4. The title compound was prepared as described in Example 43,substituting1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine(59.6 mg, 0.22 mmol) for 3-formylphenylboronic acid in Step 2.Subsequent deprotection as described for Example 43, Step 4, furnishedthe title compound as a brown powder, 54.2 mg, 62.4%.

LC/MS: RT=1.33 Min (230 nm), m/z=463 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.94-2.02 (m, 4H), 5.41 (s, 2H), 6.52-6.57 (dd, 1H),6.77-6.80 (m, 1H), 6.87-6.91 (d, 1H), 7.24-7.41 (m, 6H), 7.82 (s, 1H),8.10 (s, 1H), 8.45-8.48 (m, 2H), 8.50-8.52 (d, 1H), 9.91 (s, 1H), 11.47(br s, 1H) 4 protons not seen

Example 64 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 4. The title compound was prepared as described in Example 43,substituting1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(41.6 mg, 0.2 mmol) for 3-formylphenylboronic acid, aqueous sodiumcarbonate solution, 2M (0.18 mL, 0.36 mmol),tetrakis(triphenylphosphine)palladium(0) (10.5 mg, 9.1 μMol) forPd(dppf)Cl₂, 1,4-dioxane (2 mL) for THF/H₂O (10:1) and heating at 150°C. for 20 minutes under microwave irradiation, in Step 2. Subsequentdeprotection as described for Example 43, Step 4, furnished the titlecompound as a yellow powder, 32.6 mg, 52.6%.

LC/MS: RT=1.01 Min (230 nm), m/z=398 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 3.88 (s, 3H), 5.41 (s, 2H), 7.27-7.41 (m, 5H), 7.72(s, 1H), 7.84 (d, 1H), 8.09 (s, 1H), 8.12 (s, 1H), 8.27-8.30 (d, 1H),8.45-8.48 (m, 2H), 9.85 (s, 1H), 11.40 (br s, 1H)

Example 65 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared from Example 1.1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (75 mg, 0.19 mmol),pyridine-4-boronic acid (34.9 mg, 0.28 mmol), K₃PO₄, 2M aqueous solution(0.19 mL, 0.38 mmol) and Pd(dppf)Cl₂ (13.3 mg, 0.02 mmol) were combinedin 1,4-dioxane (2 mL) and thoroughly degassed. The reaction mixture washeated at 120° C. for 1 hour under microwave irradiation and then it waspartitioned between saturated aqueous sodium hydrogen carbonate andEtOAc. The organic layer was separated and the aqueous extracted withanother portion of EtOAc. The combined organics were washed with H₂O,saturated aqueous sodium chloride, dried (MgSO₄) and solvent removed invacuo. This crude material was purified by flash chromatography, elutingwith DCM then 4% MeOH/DCM then 7% MeOH/DCM. Fractions found to containpure material were combined and solvent removed in vacuo to afford thedesired product as a beige solid, 30.9 mg, 41.4%.

LC/MS: RT=1.80 Min (254 nm), m/z=395 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.42 (s, 2H), 7.29-7.41 (m, 5H), 7.78 (m, 2H), 7.85(d, 1H), 8.10 (d, 1H), 8.48 (s, 1H), 8.63-8.80 (m, 4H), 9.96 (s, 1H),11.67 (br d, 1H)

Example 66 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared from Example 1, using exactly the sameprotocol as Example 65 but substituting pyridine-3-boronic acid (75 mg,0.19 mmol) for pyridine-4-boronic acid. The title compound was isolatedas a beige solid, 24.8 mg, 33.2%.

LC/MS: RT=1.93 Min (254 nm), m/z=395 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.41 (s, 2H), 7.28-7.41 (m, 5H), 7.49-7.54 (m, 1H),7.85 (d, 1H), 8.10 (d, 1H), 8.11-8.15 (m, 1H), 8.47 (s, 1H), 8.55-8.60(m, 3H), 8.94 (dd, 1H), 9.91 (s, 1H), 11.59 (br d, 1H)

Example 67 1-(3-Methoxy-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to the route outlined inScheme 1, and using the methodology described for Example 1,substituting 1-(3-methoxy-benzyl)-1H-pyrazole-4-carboxylic acid (120.8mg, 0.52 mmol) for 1-benzyl-1H-pyrazole-4-carboxylic acid in Step 1. Thetitle compound was isolated as a pale brown solid, 73.6 mg, 36.6%.

LC/MS: RT=2.35 Min (254 nm), m/z=426.3 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 3.75 (s, 3H), 5.37 (s, 2H), 6.83-6.90 (m, 3H), 7.29(t, 1H), 7.84 (d, 1H), 8.08 (s, 1H), 8.28 (d, 1H), 8.44 (s, 1H), 8.48(d, 1H), 9.88 (s, 1H), 11.69 (s, 1H)

Example 68 1-(2-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to the route outlined inScheme 1, and using the methodology described for Example 1,substituting 1-(2-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (114.5mg, 0.52 mmol), prepared in a similar way to14-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid as described in Example17, for 1-benzyl-1H-pyrazole-4-carboxylic acid in Step 1. In Step 3, theproduct precipitated following dilution of the reaction mixture withH₂O. It was separated via filtration, washed well with H₂O and Et₂O thendried in vacuo at 40° C. to afford the title compound as a pale orangesolid, 93.1 mg, 47.7%.

LC/MS: RT=2.27 Min (254 nm), m/z=414.3 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.47 (s, 2H), 7.20-7.32 (m, 3H), 7.41 (q, 1H), 7.84(d, 1H), 8.07 (s, 1H), 8.28 (d, 1H), 8.44 (s, 1H), 8.48 (d, 1H), 9.89(s, 1H), 11.70 (s, 1H)

Example 69 1-(2-Cyano-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to the route outlined inScheme 1, and using the methodology described for Example 1,substituting 1-(2-cyano-benzyl)-1H-pyrazole-4-carboxylic acid (118.2 mg,0.52 mmol), prepared in a similar way to14-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid as described in Example17, for 1-benzyl-1H-pyrazole-4-carboxylic acid in Step 1. In Step 3,following the usual aqueous work up, the crude material was trituratedin Et₂O, filtered, washed with Et₂O and dried in vacuo at 40° C. toafford the title compound as a solid, 54.8 mg, 27.7%.

LC/MS: RT=2.20 Min (254 nm), m/z=423.3 [M+H]. Total run time 3.75 min(short pos/neg), (HP1100.

¹H NMR (d₆ DMSO): δ 5.62 (s, 2H), 7.36 (d, 1H), 7.56 (td, 1H), 7.73 (td,1H), 7.84 (d, 1H), 7.91 (dd, 1H), 8.12 (s, 1H), 8.28 (d, 1H), 8.48 (d,1H), 8.50 (s, 1H), 9.93 (s, 1H), 11.71 (br s, 1H)

Example 70 1-(1H-Pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to the route outlined inScheme 1, and using the methodology described for Example 1,substituting potassium1-(1H-pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylate (61.2 mg, 0.32 mmol)for 1-benzyl-1H-pyrazole-4-carboxylic acid in Step 1. In Step 3,following the usual aqueous work up, the crude material was purified viaautomated column chromatography eluting with DCM to 20% MeOH/DCM(gradient). Fractions found to contain product were combined and solventremoved in vacuo and the residue further purified via preparative HPLCat pH 9 to afford the title compound as white solid, 15.4 mg, 12.5%.

Preparation of potassium1-(1H-pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylate Step 1: Preparationof 1-methanesulfonyl-1H-pyrrole-2-carbaldehyde

A solution of pyrrole carboxaldehyde (1.0 g, 10.5 mmol) in THF (20 mL)was added drop wise to a suspension of sodium hydride, 60% dispersion inmineral oil (484 mg, 12.1 mmol) and THF (60 mL) and the mixture stirredfor 15 mins at RT. Methane sulfonyl chloride (1.69 g, 14.72 mmol) wasadded drop wise and the reaction was stirred for a further 1 hour at RT.The reaction was diluted with H₂O and concentrated under reducedpressure. The residual aqueous was extracted with DCM (×5) and thecombined extracts were then washed successively with saturated aqueoussodium bicarbonate, H₂O and with saturated aqueous sodium chloride. Theorganics were dried over MgSO₄ and concentrated under reduced pressureto afford an oil that was purified by automated flash chromatographyeluting with of iso-hexane to 30% EtOAc/iso-hexane (gradient). Fractionsfound to contain pure product were combined and solvent removed in vacuoto afford the title compound as a colourless oil, 1.3 g, 71.4%.

Step 2: Preparation of (1-methanesulfonyl-1H-pyrrol-2-yl)-MeOH

1-Methanesulfonyl-1H-pyrrole-2-carbaldehyde (1.3 g, 7.51 mmol) wasstirred in a mixture of DCM (180 mL) and MeOH (63 ml) at 0° C. Sodiumborohydride (428 mg, 11.3 mmol) was added in portions and the reactionmixture was left to stir at 0° C. for 1.5 hours. The reaction mixturewas diluted with DCM (80 mL) and oxalic acid, 5% aqueous solution (200mL) was added drop wise and stirring continued at 0° C. for a further 15minutes, before allowing the reaction mixture to warm to RT. The organiclayer was separated, washed with H₂O (2×250 ml), dried over MgSO₄ andconcentrated under reduced pressure to afford the title compound as pinkcrystals, 0.865 g, 65.8%.

Step 3: Preparation of1-(1-methanesulfonyl-1H-pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylic acidethyl ester

DIPEA (1.29 mL, 7.41 mmol) was added to a solution of(1-methanesulfonyl-1H-pyrrol-2-yl)-MeOH (865 mg, 4.94 mmol) in DCM (27mL) and cooled to 0° C. Methanesulfonyl chloride (0.57 mL, 7.41 mmol)was added drop wise and the reaction was stirred at 0° C. for 20 minutesand RT for 30 minutes. The reaction mixture was diluted with DCM andwashed successively with ice cold H₂O, cold 10% aqueous hydrochloricacid solution and followed by saturated aqueous sodium hydrogenbicarbonate. The organics were dried over MgSO₄ and concentrated underreduced pressure (low temperature) to afford2-chloromethyl-1-methanesulfonyl-1H-pyrrole as an orange oil which wasused immediately as the compound can polymerize on standing. A solutionof 2-chloromethyl-1-methanesulfonyl-1H-pyrrole (1.02 g, 5.27 mmol) inacetone (11 mL) was added to a suspension of 1H-pyrazole-4-carboxylicacid ethyl ester (703 mg, 5.02 mmol) and potassium carbonate (2.78 g,20.1 mmol) in acetone (10 mL). Stirring was continued for 70 hours at RTand then the reaction mixture was filtered and the filter cake washedthrough with EtOAc. The filtrate was concentrated under reduced pressureand the residue was taken up in EtOAc, washed with H₂O, dried (MgSO₄)and concentrated under reduced pressure. The crude material was purifiedby automated flash chromatography eluting with iso-hexane toEtOAc/iso-hexane to EtOAc (gradient). Fractions containing pure productwere combined and concentrated in vacuo to afford the desired compoundas an orange oil that solidified on standing, 442 mg, 29.6%. Fractionscontaining product and an impurity were combined and concentrated invacuo and the residue further purified via SCX-2 ion exchange columngiving a further 359 mg, 24.1%, of title compound as an off white solid.

Step 4: Preparation of Potassium1-(1H-pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylate

1-(1-Methanesulfonyl-1H-pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylic acidethyl ester (801 mg, 2.69 mmol) was dissolved in a mixture of MeOH:THF(1:1, 20 mL) and a solution of potassium hydroxide (301.8 mg, 5.38 mmol)in H₂O (2 mL) was added. The reaction mixture was then refluxed for 4hours, cooled and concentrated in vacuo. The residue was dried in adessicator at 60° C. for 18 hours to give the title compound as a solid,860 mg, 93.5%. It was assumed by the recovery, and reactionstoichiometry to be predominantly the desired title compound with 2equivalents of KOH present and it was used without further purification.

Step 5: Preparation of title compound:1-(1H-pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-ylamine (101.8 mg, 0.48 mmol) andpotassium 1-(1H-pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxylate (61.2 mg,0.179 mmol) were stirred in DMF (4 mL) and triethylamine (97 mg, 0.13ml, 0.96 mmol) was added followed by HATU (183 mg, 0.48 mmol). Thereaction mixture was left to stir at RT for 72 hours and diluted withEtOAc. The organics were separated and the aqueous extracted with afurther portion of EtOAc. The combined extracts were washed withsaturated aqueous sodium chloride (×3), dried (MgSO₄) and concentratedin vacuo. The crude material was purified automated flash chromatographyeluting with DCM to 20% MeOH/DCM (gradient). Fractions containingproduct were combined and concentrated in vacuo and the residue wasfurther purified by preparative HPLC at pH9 to afford the title compoundas a white solid, 15.4 mg, 22.3%.

LC/MS: RT=1.09 Min (254 nm), m/z=386.0 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 5.28 (s, 2H), 6.00 (m, 1H), 6.13 (s, 1H), 6.75 (m,1H), 7.83 (d, 1H), 8.04 (s, 1H), 8.23 (s, 1H), 8.27 (d, 1H), 8.47 (d,1H), 9.88 (s, 1H), 11.03 (s, 1H), 11.69 (s, 1H)

Example 71 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to the route outlined inScheme 1, and using the methodology described for Example 1,substituting 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (45.7 mg,0.21 mmol), as described in Example 17, for1-benzyl-1H-pyrazole-4-carboxylic acid in Step 1. The title compound wasisolated as a brown solid, 26.7 mg, 34.2%.

LC/MS: RT=2.26 Min (270 nm), m/z=416.3 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.40 (s, 2H), 7.19-7.23 (m, 2H), 7.35-7.38 (m, 2H),7.84 (d, 1H), 8.08 (s, 1H), 8.28 (d, 1H), 8.45 (s, 1H), 8.48 (d, 1H),9.88 (s, 1H), 11.69 (br s, 1H)

Example 72 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 1, and using the methodology described for Example 1,substituting 5-methyl-1H-pyrrolo[2,3-b]pyridine (1.06 g, 8.02 mmol) for5-bromo-1H-pyrrolo[2,3-b]pyridine in Step 1. In Step 2, the methodologyfrom Example 6, Step 6, substituting5-methyl-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.42 g, 8.02 mmol) for5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine, was used. The titlecompound was isolated as a cream solid, 22.7 mg, 20.2%, following theprotocol described for Example 1, Step 3, substituting5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (50 mg, 0.34 mmol) for5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylamine.

LC/MS: RT=2.04 Min (270 nm), m/z=332.4 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 2.38 (s, 3H), 5.40 (s, 2H), 7.29-7.40 (m, 5H), 7.69(d, 1H), 7.97-7.98 (m, 1H), 8.06-8.08 (m, 2H), 8.44 (s, 1H), 9.80 (s,1H), 11.25 (br s, 1H)

Example 73 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 1, and using the methodology described for Example 1,in Steps 1 and 2, substituting 5-chloro-1H-pyrrolo[2,3-b]pyridine (400mg, 2.62 mmol) for 5-bromo-1H-pyrrolo[2,3-b]pyridine in Step 1.

Step 3: Preparation of title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid (5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylamine (37.4 mg, 0.22 mmol), HATU(95.1 mg, 0.2 mmol) and acetonitrile (5 mL) were combined in a microwavevial. 1-Benzyl-1H-pyrazole-4-carboxylic acid (49.6 mg, 0.25 mmol) andDIPEA (0.09 mL, 0.50 mmol) were added, and contents degassed. Thereaction was then heated at 80° C. under microwave irradiation for 1hour. The reaction was partitioned between EtOAc and H₂O and theorganics separated. The aqueous was extracted with a further portion ofEtOAc and the combined extracts were washed with H₂O, saturated aqueoussodium chloride, dried (MgSO₄) and concentrated in vacuo. The crudematerial was purified by automated column chromatography eluting with30% EtOAc/iso-hexane to 100% EtOAc. Fractions containing pure materialwere combined, concentrated in vacuo to afford the desired compound as abrown powder, 24 mg, 30.6%.

LC/MS: RT=2.19 Min (270 nm), m/z=352 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.42 (s, 2H), 7.29-7.41 (m, 5H), 7.86 (s, 1H), 8.09(s, 1H), 8.23 (s, 1H), 8.35 (s, 1H), 8.46 (s, 1H), 9.89 (s, 1H), 11.70(s, 1H)

Example 74 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 1, and using the methodology described for Example73, in Step 1.

Step 2: Preparation of 5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylamine

Tin (II) chloride dihydrate (8.57 g, 38 mmol) was added in portions to amixture of 5-chloro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.5 g, 7.59 mmol)in 6N HCl (60 mL) at 5° C. and the reaction was stirred at RT for 2hours. The reaction mixture was cooled and diluted with H₂O (300 mL)then basified to pH8 by the careful addition of 50% aqueous NaOHsolution. The mixture was then extracted with DCM/IPA (3:1, 4×150 mL)and the combined extracts were washed with saturated aqueous sodiumchloride, dried (MgSO₄) and solvent removed in vacuo to afford the titlecompound as a green solid, 1.25 g, 98.2%.

Step 3: Preparation of title compound:1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylamine (40.0 mg, 0.24 mmol) wasstirred in DMF (3.0 mL), with Et₃N (0.07 mL, 0.48 mmol) and1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (57.8 mg, 0.26 mmol),which was prepared in Example 17. HATU (91.3 mg, 0.24 mmol) was addedand the reaction was stirred at RT for 2 hours. The reaction mixture wasdiluted with H₂O, and extracted with EtOAc (3×30 mL). The combinedextracts were washed with saturated aqueous sodium bicarbonate,saturated aqueous sodium chloride (4×60 mL), dried (MgSO₄) and solventremoved in vacuo. The crude material was purified by automated columnchromatography, eluting with DCM to 5% MeOH/DCM (gradient). Fractionscontaining pure product were combined and concentrated in vacuo toafford the title compound as a pale brown solid, 58.7 mg, 66.5%.

LC/MS: RT=2.23 Min (270 nm), m/z=370.3 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 5.40 (s, 2H), 7.19-7.23 (m, 2H), 7.35-7.39 (m, 2H),7.85 (d, 1H), 8.08 (s, 1H), 8.21 (d, 1H), 8.33 (d, 1H), 8.44 (s, 1H),9.88 (s, 1H), 11.69 (br s, 1H)

Example 75 1-(3-methoxy-benzyl)-1H-pyrazole-4-carboxylic acid(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 1, and using the methodology described for Example74, substituting 1-(3-methoxy-benzyl)-1H-pyrazole-4-carboxylic acid(72.8 mg, 0.31 mmol) for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylicacid in Step 3. The title compound was isolated as a white solid, 24 mg,21.1% following trituration with EtOAc.

LC/MS: RT=2.42 Min (254 nm), m/z=382 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 3.75 (s, 3H), 5.38 (s, 2H), 6.88 (m, 3H), 7.30 (t,7.83, 1H), 7.87 (s, 1H), 8.09 (s, 1H), 8.23 (s, 1H), 8.35 (s, 1H), 8.44(s, 1H), 9.88 (s, 1H), 11.71 (s, 1H)

Example 76 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-((S)-1-methyl-Pyrrolidin-2-ylmethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared according an analogous route to thatoutlined in Scheme 6.

The title compound was prepared from 1-benzyl-1H-pyrazole-4-carboxylicacid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide,the product of Step 1 in Example 43.

Step 1: Preparation of(5)-1-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-pyrrolidine

To a solution of4-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (150 mg, 0.68mmol), (S)-(−)-1-methyl-2-pyrrolidineMeOH (117.8 mg, 1.02 mmol) andtriphenylphosphine (268.2 mg, 1.02 mmol) in THF (3 mL) was added DIAD(206.7 mg, 2 mL, 1.02 mmol) drop wise at 0° C. The resulting solutionwas stirred at room temperature for 36 hours and the reaction mixtureconcentrated in vacuo. The crude material was purified by automatedcolumn chromatography eluting iso-hexane to 50% EtOAc/iso-hexane(gradient). The title compound was isolated as a white solid, 220 mg,100%.

Step 2: Preparation of title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid{5-[3-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

1-benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(115 mg, 0.21 mmol),(5)-1-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-pyrrolidine(99.4 mg, 0.31 mmol), potassium carbonate (86.6 mg, 0.63 mmol), THF (4mL) and H₂O (0.4 mL) were combined in a microwave vial/. The mixture wasdegassed, Pd(dppf)Cl₂ (7.64 mg, 0.01 mmol) added and the reaction heatedat 130° C. for 1 hour under microwave irradiation. The reaction mixturewas diluted with DCM and washed with saturated aqueous sodium chloride.The organics were separated, dried (MgSO₄) and concentrated in vacuo.The crude material was purified via automated column chromatographyeluting with DCM to 10% MeOH/DCM (gradient). This afforded a mixture oftwo compounds, 1-benzyl-1H-pyrazole-4-carboxylic acid[5-[3-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amideand 1-benzyl-1H-pyrazole-4-carboxylic acid[5-[3-(1-methyl-piperidin-3-yloxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amideas a brown glass. This was taken up in MeOH (5 mL) and transferred to amicrowave vial. K₂CO₃ (100.9 mg, 0.73 mmol) was added and the contentsheated at 80° C. for 30 minutes under microwave irradiation. Thereaction mixture was concentrated in vacuo to one quarter of volume anddiluted with H₂O. Upon standing a precipitate formed, which was filteredoff and washed with H₂O and then Et₂O. The powder was dried and purifiedvia automated column chromatography eluting with DCM to 19% MeOH/DCM(gradient), to give the title compound as a white powder, 7 mg, 6.6%.Example 77 (below), 1-benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(1-methyl-piperidin-3-yloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide,was also isolated from the same column as a solid, 8 mg, 7.6%.

LC/MS: RT=1.00 Min (230 nm), m/z=507 [M+H]. Total run time 1.9 min(super short pos), H P1200.

¹H NMR (d₆ DMSO): δ 1.62-1.81 (m, 3H), 1.96-2.08 (m, 1H), 2.96-3.12 (m,1H), 3.9-4.15 (m, 2H), 5.42 (s, 2H), 6.93-6.98 (m, 1H), 7.22-7.42 (m,8H), 7.82-7.85 (m, 1H), 8.10 (s, 1H), 8.48 (s, 1H), 8.51-8.57 (m, 2H),9.92 (br s, 1H), 11.51 (br s, 1H) 5 protons not seen

Example 77 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(1-methyl-piperidin-3-yloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was isolated from the crude reaction mixture asdescribed in Example 76, Step 2, as a solid, 8 mg, 7.6%.

LC/MS: RT=1.00 Min (230 nm), m/z=507 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.31-1.42 (m, 1H), 1.50-1.62 (s, 1H), 1.67-1.76 (m,1H), 1.95-2.10 (m, 3H), 2.19 (s, 3H), 2.86-2.92 (m, 1H), 4.46-4.54 (m,1H), 5.41 (s, 2H), 6.94-6.98 (m, 1H), 7.22-7.41 (m, 8H), 7.82-7.84 (d,1H), 8.10 (s, 1H), 8.48 (s, 1H), 8.51-8.55 (m, 2H), 9.91 (br s, 1H),11.50 (br s, 1H) 1 proton not seen

Example 78 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(3-dimethylamino-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared from 1-benzyl-1H-pyrazole-4-carboxylicacid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide,the product of Step 1 in Example 43.

Step 1: Preparation of: 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-hydroxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(1.0 g, 1.82 mmol), 4-hydroxyphenylboronic acid (0.3 g, 2.18 mmol) andK₂CO₃ (0.75 g, 5.45 mmol) were combined in THF/H₂O (14 mL: 1.4 mL) andthoroughly degassed. Pd(dppf)Cl₂ (0.067 mg, 0.09 mmol) was added and themixture degassed again before heating at 120° C. for 1 hour undermicrowave irradiation. 4-Hydroxyphenylboronic acid (0.15 g, 1.09 mmol)was added and the mixture degassed again before heating at 120° C. for 2hours and at 140° C. for 1 hour under microwave irradiation. Thereaction was diluted with saturated aqueous sodium hydrogen bicarbonate(100 mL) and extracted with EtOAc (2×100 mL). The combined organics werewashed with saturated aqueous sodium chloride, dried (MgSO₄) and solventremoved in vacuo. The crude material was purified by flashchromatography, eluting with DCM to 50% EtOAc/DCM (gradient). Fractionsfound to contain product were combined and solvent removed in vacuo. Theresidue was triturated using the minimum amount of ethanol to afford thedesired compound as a as a white solid, 0.33 g, 32.6%.

Step 2: Preparation of: 1-Benzyl-1H-pyrazole-4-carboxylic acid[5-[4-(3-dimethylamino-propoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(100 mg, 0.18 mmol) was stirred in DMF (4 mL) with K₂CO₃ (73.6 mg, 0.53mmol). To this was added (3-chloro-propyl)-dimethylamine hydrochloride(36.5 mg, 0.23 mmol) and the reaction was then heated at 50° C. for 16hours. The reaction was then cooled, concentrated in vacuo, and theresidue partitioned between saturated aqueous sodium hydrogen carbonate(30 mL) and EtOAc (40 mL). The organics were separated and the aqueousextracted with another portion of EtOAc (40 mL). The combined organicswere washed with saturated aqueous sodium chloride, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography eluting with DCM then 10% MeOH/DCM and finally 6% ammoniasolution, 7N in MeOH/EtOAc. The fractions containing product werecombined and concentrated in vacuo to afford the title compound as ayellow solid, 67 mg, 58.2%.

Step 3: Preparation of title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid{5-[4-(3-dimethylamino-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-[4-(3-dimethylamino-propoxy)-phenyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(67 mg, 0.10 mmol), K₂CO₃ (71.4 mg, 0.52 mmol) and MeOH (2 mL) werecombined in a microwave vial and heated at 100° C. for 30 minutes. Themixture was concentrated in vacuo and the crude material was purified bypreparative HPLC at pH 9 and then at pH 4 to afford the title compoundas a pale orange solid, 0.8 mg, 1.6%.

LC/MS: RT=1.98 Min (254 nm), m/z=495 [M+H]. Total run time 3.75 min(short pos/neg), HP1100.

¹H NMR (d₆ DMSO): δ 1.87 (m, 2H), 2.16 (s, 6H), 2.37 (t, 2H), 4.04 (t,2H), 5.41 (s, 2H), 7.04 (m, 2H), 7.27-7.41 (m, 5H), 7.62 (m, 2H), 7.80(d, 1H), 8.10 (s, 1H), 8.40 (br s, 1H), 8.43-8.50 (m, 3H), 9.92 (s, 1H),11.45 (d, 1H)

Example 79 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[1-(2-diethylamino-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared according to the route outlined inScheme 6. The title compound was prepared from1-benzyl-1H-pyrazole-4-carboxylic acid[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide,the product of Step 1 in Example 60.

Step 1: Preparation of [2-(4-Bromo-pyrazol-1-yl)-ethyl]-diethyl-amine

Cs₂CO₃ (1.66 g, 5.1 mmol) was added to a solution of 4-bromopyrazole(0.25 g, 1.7 mmol) in DMF (2 mL) and the mixture stirred for 10 minutes.2-Bromo-N,N-diethylethylamine hydrobromide (0.577 g, 2.21 mmol) wasadded and the reaction heated at 70° C. 18 hours. The reaction wasdiluted with H₂O and extracted with DCM/IPA (4:1) (×2). The organicswere combined, washed with saturated aqueous sodium chloride (×4), dried(MgSO4) and concentrated in vacuo to afford the title compound as a paleyellow oil, 275 mg, 65.7%.

Step 2: Preparation of 1-benzyl-1H-pyrazole-4-carboxylic acid[5-[1-(2-diethylamino-ethyl)-1H-pyrazol-4-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(90 mg, 0.15 mmol), [2-(4-Bromo-pyrazol-1-yl)-ethyl]-diethyl-amine (74.2mg, 0.3 mmol), K₂CO₃) 62.5 mg, 0.45 mmol) THF (4 mL) and H₂O (0.4 mL)were combined in a microwave vial and degassed. Pd(dppf)Cl₂ (5.5 mg,0.01 mmol) was added and the contents degassed again before heating at130° C. for 1 hour under microwave irradiation. The mixture was degassedand a further portion of Pd(dppf)Cl₂ (5.5 mg, 0.01 mmol) was added anddegassed before heating at 130° C. for 30 minutes. The reaction mixturewas diluted with DCM and the organics separated. The aqueous wasextracted with another portion of DCM and the combined organics werewashed with saturated aqueous sodium chloride, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by automatedcolumn chromatography eluting with DCM to 15% MeOH/DCM (gradient) toafford the title compound, 24 mg, 25.1%.

Step 3: Preparation of title compound: 1-Benzyl-1H-pyrazole-4-carboxylicacid{5-[1-(2-diethylamino-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide(90 mg, 0.15 mmol), [2-(4-Bromo-pyrazol-1-yl)-ethyl]-diethyl-amine (24mg, 0.038 mmol), K₂CO₃ (104.1 mg, 0.75 mmol) and MeOH (3 mL) werecombined in a microwave vial and heated at 80° C. for 30 minutes. Thereaction mixture was concentrated in vacuo to one quarter volume anddiluted with H₂O. After standing for 2 hrs the solid was separated viafiltration, washed with H₂O then Et₂O and dried in vacuo to afford thetitle compound as a grey powder, 7 mg, 38.2%.

LC/MS: RT=0.92 Min (230 nm), m/z=483 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 0.90-0.95 (t, 6H), 2.79-2.84 (t, 2H), 4.14-4.19 (t,2H), 5.41 (s, 2H), 7.28-7.41 (m, 5H), 7.72 (s, 1H), 7.85 (s, 1H), 8.09(s, 1H), 8.16 (s, 1H), 8.27-8.30 (m, 1H), 8.45-8.49 (m, 2H), 9.86 (br s,1H), 11.39 (br s, 1H) 4 protons not seen

Example 80 1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide

The title compound was prepared according to the route outlined inScheme 6, and using the methodology described for Example 79,substituting 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (376.1 mg,2.21 mmol) for 2-bromo-N, N-diethylethylamine hydrobromide in Step 1.The title compound was isolated as a dark powder, 10 mg, 13.8%.

LC/MS: RT=1.15 Min (230 nm), m/z=481 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.63-1.69 (m, 4H), 2.83-2.88 (t, 2H), 4.21-4.26 (t,2H), 5.41 (s, 2H), 7.28-7.41 (m, 5H), 7.72 (s, 1H), 7.84-7.86 (s, 1H),8.09 (s, 1H), 8.18 (s, 1H) 8.28-8.31 (m, 1H), 8.45-8.49 (m, 2H), 9.87(br s, 1H), 11.40 (br s, 1H) 4 protons not seen

Example 81 1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2.

It was prepared from4-fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylamine, the product ofStep 7, in Example 31.

Step 1: Preparation of 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylicacid

4-bromomethyl pyridine hydrochloride (3.58 g, 14.17 mmol) was added to asuspension of ethyl 1H-pyrazole-4-carboxylate (1.89 g, 14.17 mmol) andcesium carbonate (10.43 g, 32 mmol) in acetone (50 mL), under a nitrogenatmosphere, and the suspension stirred for 18 hours at RT. The reactionwas diluted with H₂O and then extracted with EtOAc (×2). The combinedextracts were washed with H₂O, saturated aqueous sodium chloridesolution, dried (MgSO₄) and concentrated in vacuo. The residue wasstirred in MeOH (50 mL) and a solution of sodium hydroxide (0.896 g,22.4 mmol) H₂O (15 mL) was added. The reaction mixture was heated atreflux for 3 hours and then cooled to RT. The solvent was removed invacuo and the residue diluted with a little H₂O. The pH of the mixturewas adjusted to 4 by the careful addition of aqueous hydrochloric acidsolution, 1.0M. After stirring for 10 mins the solids were separated viafiltration, washed well with H₂O and dried in vacuo to yield the desiredtitle compound as a solid, 0.449 g. The filtrate was extracted withEtOAc (×6) and combined extracts were washed with saturated aqueoussodium chloride, dried over MgSO₄ and concentrated in vacuo to furnish afurther crop of the title compound, 0.736 g. This gave a total of 1.185g, 78%.

Step 2: Preparation of 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylicacid (5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

4-fluoro-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-ylamine (97 mg, 0.54 mmol)was stirred in DMF (5 mL). Et₃N 109 mg, 150 uL, 1.08 mmol) and1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid (119.7 mg, 0.59 mmol)were added followed by HATU (224.3 mg, 0.54 mmol). The reaction wasstirred at RT for 18 hrs and then diluted with H₂O (20 mL). The solutionwas extracted with EtOAc (2×50 mL) and 10% MeOH in DCM (2×50 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated invacuo. The residue was triturated with EtOAc to give the title compoundas a pale brown solid 125 mg, 63.7%.

Step 3: Preparation of title compound:1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (125 mg, 0.34mmol), (R)-piperidin-3-yl-carbamic acid tert-butyl ester (341.7 mg, 1.71mmol) and ^(n)BuOH (5 mL) were combined in a microwave vial and heatedunder microwave irradiation at 160° C. for 6 hours. The solvent wasremoved in vacuo and the residue was taken up in DCM (5 mL). TFA (3 mL)was added and the reaction mixture was stirred at RT for 18 hrs. Thereaction was concentrated in vacuo and taken up in DCM prior to loadingonto a SCX-2 ion exchange column. The column was washed with DCM, MeOHand the compound of interest was eluted with ammonia solution 7 N inMeOH that had been diluted to 0.5N using DCM. Fractions containingproduct were combined and concentrated in vacuo. The material wasfurther purified by automated column chromatography eluting with DCM to5% ammonia solution 7N in MeOH/5% MeOH/DCM. The fractions containingpure product were combined and concentrated in vacuo to afford the titlecompound as a pale orange solid 22 mg, 14%.

LC/MS: RT=1.35 Min (270 nm), m/z=447 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.18 (m, 1H), 1.44-1.76 (m, 5H), 2.85 (m, 2H), 3.03(m, 2H), 3.21 (d, 1H), 3.86 (s, 3H), 5.50 (s, 2H), 7.16 (m, 2H), 7.71(s, 1H), 8.06 (m, 2H), 8.55 (m, 2H), 8.63 (s, 1H), 9.76 (br s, 1H),11.22 (br s, 1H)

Example 82 1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2, and using the methodology described for Example81, substituting 1-pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid(119.7 mg, 0.59 mmol) for 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylicacid in Step 1. The title compound was isolated as an off white solid,48 mg, 26.6%.

LC/MS: RT=1.50 Min (270 nm), m/z=447 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.2 (m, 1H), 1.41-1.75 (m, 5H), 2.85 (m, 2H), 3.03(t, 2H), 3.21 (d, 1H), 3.86 (s, 3H), 5.47 (s, 2H), 7.40 (dd, 1H),7.67-7.72 (m, 2H), 8.04 (m, 2H), 8.52-8.62 (m, 3H), 9.74 (br s, 1H),11.20 (br s, 1H)

Example 83 1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2, and using the methodology described for Example81, substituting 1-pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid(119.7 mg, 0.59 mmol) for 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylicacid in Step 1. The title compound was isolated as an off white solid,56 mg, 34%.

LC/MS: RT=1.60 Min (270 nm), m/z=447 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.2 (m, 1H), 1.48-1.77 (m, 5H), 2.86 (m, 2H), 3.05(m, 2H), 3.21 (d, 1H), 3.86 (s, 3H), 5.52 (s, 2H), 7.14 (d, 1H), 7.33(dd, 1H), 7.74 (s, 1H), 7.81 (t, 1H), 8.02 (s, 1H), 8.07 (s, 1H), 8.56(m, 2H), 9.78 (br s, 1H), 11.21 (br s, 1H)

Example 84 1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amid

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2, using the methodology described for Example 24,substituting 1-pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid (344.5mg, 1.7 mmol) for 1-benzyl-1H-pyrazole-4-carboxylic acid in Step 6.After the usual work up as described in Step 7, the crude material wastaken up in DCM and loaded onto a SCX-2 ion exchange column. The columnwas washed with DCM, MeOH and the compound of interest was eluted withammonia solution 7 N in MeOH that had been diluted to 0.5N using DCM.Fractions containing product were combined and concentrated in vacuo.The residue was further purified by automated column chromatographyeluting with 2% Et₃N in DCM to 20% MeOH/2% Et₃N in DCM (gradient).Fractions containing pure material were combined and concentrated invacuo to afford the title compound as a pale yellow solid, 52 mg, 21.4%.

LC/MS: RT=1.59 Min (270 nm), m/z=451 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.19 (m, 2H), 1.46 (m, 1H), 1.69 (m, 2H), 2.92 (m,2H), 3.12 (m, 2H), 5.48 (s, 2H), 7.40 (dd, 1H), 7.67-(dt, 1H), 7.71 (s,1H), 8.06 (s, 1H), 8.08 (s, 1H), 8.52-8.58 (m, 3H), 9.73 (br s, 1H),11.69 (br s, 1H) 2 protons not seen

Example 85 1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2, using the methodology described for Example 24,substituting 1-pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid (344.5mg, 1.7 mmol) for 1-benzyl-1H-pyrazole-4-carboxylic acid in Step 6.After the usual work up as described in Step 7, the crude material wastaken up in DCM and loaded onto a SCX-2 ion exchange column. The columnwas washed with DCM, MeOH and the compound of interest was eluted withammonia solution 7 N in MeOH that had been diluted to 0.5N using DCM.Fractions containing product were combined and concentrated in vacuo.The residue was further purified by automated column chromatographyeluting with DCM to 12% MeOH/DCM (gradient). Fractions containingproduct were combined and concentrated in vacuo. The residue was furtherpurified by preparative HPLC at pH4. Fractions containing pure materialwere combined and concentrated in vacuo to afford a mixture of desiredcompound and 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[5-chloro-4-((R)-3-formylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide.This material was stirred in the minimum amount of MeOH and thenhydrochloric acid solution, 4M in 1,4-dioxane (2 mL) was added. Thereaction was stirred at RT for 18 hours and the solvent was removed invacuo. The residue was taken up in DCM, washed with 5% aqueous ammoniasolution, dried (MgSO₄) and concentrated in vacuo. The residue wasfurther purified by automated column chromatography eluting with 2% Et₃Nin DCM to 20% MeOH/2% Et₃N in DCM (gradient). Fractions containing purematerial were combined and concentrated in vacuo to afford the titlecompound as a pale yellow solid, 52 mg, 13.2%.

LC/MS: RT=1.52 Min (270 nm), m/z=451 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.19 (m, 2H), 1.48 (m, 1H), 1.69 (m, 2H), 2.25 (brs, 2H), 2.92 (m, 2H), 3.13 (m, 2H), 5.50 (s, 2H), 7.15 (m, 2H), 7.72 (s,1H), 8.09 (m, 2H), 8.57 (m, 3H), 9.74 (br s, 1H), 11.71 (br s, 1H)

Example 86 1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2, using the methodology described for Example 85,substituting 1-pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid (344.5mg, 1.7 mmol) for 1-benzyl-1H-pyrazole-4-carboxylic acid in Step 6. Thetitle compound was isolated as a pale yellow solid, 30 mg, 12.3%.

LC/MS: RT=1.69 Min (270 nm), m/z=451 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.20 (m, 2H), 1.50 (m, 1H), 1.72 (m, 2H), 2.08 (brs, 2H), 2.92 (m, 2H), 3.15 (m, 2H), 5.52 (s, 2H), 7.13 (d, 1H), 7.37(dd, 1H), 7.75 (s, 1H), 7.81 (m, 1H), 8.04 (s, 1H), 8.09 (s, 1H), 8.56(m, 2H), 9.79 (br s, 1H), 11.68 (br s, 1H)

Example 87 1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to an analogous route to thatoutlined in Scheme 2.

It was prepared from4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, the product ofStep 2, in Example 6.

Step 1: Preparation of 4-Fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridine

sec-Butyllithium solution, 1.4M in cyclohexane (8.76 mL, 12.26 mmol) wasadded drop wise to a solution of4-fluoro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (2.05 g, 7.01mmol) in THF (75 mL) at −78° C. The reaction was stirred at −78° C. for30 minutes and then methyl iodide (2.49 g, 1.09 mL, 17.52 mmol) wasadded drop wise and the reaction was stirred at −78° C. for a further 45minutes. The reaction was quenched by the addition of saturated aqueousammonium chloride (50 mL) and the reaction allowed to attain RT. Themixture was extracted with EtOAc (×3) and the combined extracts washedwith saturated aqueous sodium chloride, dried (MgSO₄) and concentratedin vacuo. The residue was taken up in THF (50 mL) and tetrabutylammoniumfluoride solution, 1.0M in THF (7.01 mL, 7.01 mmol) was added drop wiseat RT. The reaction mixture was stirred at RT for 30 minutes and thenpartitioned between H₂O and EtOAc. The organic layer was separated andthe aqueous was extracted with more EtOAc. The combined organic phaseswere washed with saturated aqueous sodium chloride, dried (MgSO₄) andconcentrated in vacuo. The residue was stirred in DCM/iso-hexane (1:1),filtered and washed with DCM/iso-hexane (1:1) prior to drying in vacuo.This afforded the title compound as a white powder, 0.561 g, 53.3%.

Step 2: Preparation of4-fluoro-5-methyl-3-nitro-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared using the methodology described forExample 6, substituting 4-fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridine (600mg, 4 mmol) for 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine, in Step 5.The title compound was isolated as a pale yellow powder, 609 mg, 78.1%.

Step 3: Preparation of4-fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine

The title compound was prepared using the methodology described forExample 6, substituting4-fluoro-5-methyl-3-nitro-1H-pyrrolo[2,3-b]pyridine (277 mg, 1.42 mmol)for 5-Bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine, in Step 6. Thetitle compound was isolated as a brown powder, 230 mg, 98.1%.

Step 4: Preparation of 1-benzyl-1H-pyrazole-4-carboxylic acid(4-fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide

4-Fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylamine (230 mg, 1.39 mmol)was stirred in DMF (5 mL) with DIPEA (0.462 mL, 2.79 mmol) and1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid (270 mg, 1.33 mmol).HATU (582 mg, 153 mmol) was added and the reaction was stirred at RT for2 hours. The reaction mixture was diluted with H₂O, and extracted withDCM/IPA (4:1) (×2). The combined extracts were washed with saturatedaqueous sodium bicarbonate, saturated aqueous sodium chloride, dried(MgSO₄) and solvent removed in vacuo to afford a black residue. This wastriturated with MeOH/H₂O (1:1), filtered and washed with iso-hexaneprior to drying in vacuo at 40° C. This afforded the title compound as abrown powder, 198 mg, 40.6%.

Step 5: Preparation of title compound:1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

1-Benzyl-1H-pyrazole-4-carboxylic acid(4-fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide (198 mg, 0.57mmol), p-toluenesulfonic acid monohydrate (430 mg, 2.26 mmol),(R)-piperidin-3-yl-carbamic acid tert-butyl ester (565.9 mg, 2.83 mmol)and NMP (6 mL) were heated in a sealed tube at 160° C. for 7 hours. Themixture was purified by automated column chromatography eluting with DCMto 45% MeOH/DCM (gradient). The fractions containing product werecombined and concentrated in vacuo. This still crude material was takenup in the minimum amount of DCM and Et₃N (217.8 mg, 0.3 mL, 2.15 mmol)was added. The mixture was stirred at RT and di-tert-butyl dicarbonate(150 mg, 0.69 mmol) was added followed by DMAP (5 mg). This was stirredfor 1 hour, diluted with DCM and washed with H₂O, saturated aqueoussodium chloride, dried (MgSO₄) and concentrated in vacuo. This crudematerial was purified via automated column chromatography eluting withDCM to 10% MeOH/DCM (gradient). The fractions containing the higherrunning mono boc product were combined and concentrated in vacuo. Theresidue was taken up in hydrochloric acid solution, 1.25M in MeOH (2 mL)and heated under microwave irradiation at 80° C. for 30 minutes. Thesolvent was removed in vacuo and residue taken up in minimum volume ofMeOH and applied to a SCX-2 ion exchange cartridge. This was washed withMeOH and desired compound eluted with 4:1 DCM/7N NH₃ in MeOH andconcentrated in vacuo. Acetonitrile was added to the residue and aftersonication for 10 minutes a fine precipitate formed. This was pelletedin a centrifuge and, after the liquors were decanted off, the solidswere washed with Et₂O and filtered to give the title compound as a beigepowder, 4.1 mgs, 1.7%.

LC/MS: RT=0.41 Min (230 nm), m/z=431 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 1.11-1.22 (m, 1H), 1.43-1.54 (m, 1H) 1.64-1.77 (m,2H), 2.36 (s, 3H), 2.78-2.85 (m, 1H), 2.85-2.93 (m, 1H), 3.00-3.05 (m,2H), 3.17-3.24 (m, 1H), 5.51 (s, 2H), 7.13-7.16 (m, 2H), 7.68 (s, 1H),7.93 (s, 1H), 8.07 (s, 1H), 8.54-8.57 (m, 2H), 8.59 (br s, 1H), 9.78 (brs, 1H), 11.28 (br s, 1H) 2 protons not seen

Example 88 1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared using the methodology described forExample 87, substituting 1-pyridin-3-ylmethyl-1H-pyrazole-4-carboxylicacid (406 mg, 2 mmol) for 1-pyridin-4-ylmethyl-1H-pyrazole-4-carboxylicacid, in Step 4. It was isolated as a beige powder, 0.88 mgs, 0.63%.

LC/MS: RT=0.65 Min (230 nm), m/z=431 [M+H]. Total run time 1.9 min(super short pos), H P1200.

¹H NMR (d₆ DMSO): δ 1.11-1.23 (m, 1H), 1.40-1.52 (m, 1H) 1.63-1.77 (m,2H), 2.36 (s, 3H), 2.77-2.85 (m, 1H), 2.85-2.94 (m, 1H), 2.99-3.06 (m,2H), 3.16-3.25 (m, 1H), 5.47 (s, 2H), 7.38-7.44 (m, 1H), 7.65-7.70 (m,2H), 7.93 (s, 1H), 8.03 (s, 1H), 8.51-8.62 (m, 3H), 9.76 (br s, 1H),11.27 (br s, 1H) 2 protons not seen

Example 89 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 7.

It was made from[(R)-1-(3-amino-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester, the product of Step 5, in Example 32.

Step 1: Preparation of[(R)-1-(3-{[1-(4-fluoro-benzyl)-1H-pyrazole-4-carbonyl]-amino}-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester

To a solution of[(R)-1-(3-amino-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester (92 mg, 0.25 mmol),1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (61.6 mg, 0.28 mmol)and Et3N (69.6 μL, 0.5 mmol) in DMF (5 ml) was added HATU (95.1 mg, 0.25mmol) and the reaction mixture was stirred at RT for 18 hours. Thereaction mixture was concentrated in vacuo and the residue taken up inEtOAc (50 ml). It was washed with H₂O, saturated aqueous sodiumchloride, dried (MgSO₄) and concentrated in vacuo. The crude materialwas purified by automated column chromatography eluting with 30%EtOAc/iso-hexane to EtOAc (gradient). Fractions containing pure productwere combined and concentrated in vacuo to afford the title compound asa brown solid, 82 mg, 57.2%.

Step 2: Preparation of title compound:1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

To a solution of((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-methoxy-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (81 mg, 0.14 mmol) in DCM (5 mL) was added TFA (1mL) at RT. The reaction mixture was stirred for a further 2 hours at RTand then concentrated in vacuo. The residue was taken up in DCM, washedwith 5% aqueous ammonia solution, saturated aqueous sodium chloride,dried (MgSO₄) and concentrated in vacuo. The crude material was purifiedby automated column chromatography eluting with DCM to 20% MeOH(containing 5% 7N NH3 in MeOH) (gradient). Fractions containing pureproduct were combined and concentrated in vacuo to afford the titlecompound as a white solid, 34 mg, 51%.

LC/MS: RT=1.81 Min (270 nm), m/z=464 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.18 (m, 1H), 1.45-1.71 (m, 5H), 2.85 (m, 2H), 3.03(m, 2H), 3.21 (d, 1H), 3.86 (s, 3H), 5.40 (s, 2H), 7.21 (m, 2H), 7.34(m, 2H), 7.72 (s, 1H), 8.01 (s, 1H), 8.06 (s, 1H), 8.55 (s, 1H), 9.73(br s, 1H), 11.21 (br s, 1H)

Example 90 1-(3-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 7, using the methodology described for Example 89, substituting1-(3-methyl-benzyl)-1H-pyrazole-4-carboxylic acid (79 mg, 0.365 mmol)for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, in Step 1. Thetitle compound was isolated as a white solid, 59 mg, 64.7%.

LC/MS: RT=1.86 Min (270 nm), m/z=460 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.19 (m, 1H), 1.44-1.75 (m, 5H), 2.29 (s, 3H), 2.85(m, 2H), 3.03 (t, 2H), 3.21 (d, 1H), 3.86 (s, 3H), 5.36 (s, 2H),7.07-7.14 (m, 3H), 7.26 (t, 1H), 7.73 (s, 1H), 8.00 (s, 1H), 8.06 (s,1H), 8.55 (s, 1H), 9.74 (br s, 1H), 11.20 (br s, 1H)

Example 91 1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 7, using the methodology described for Example 89, substituting1-(3-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (80.4 mg, 0.365 mmol)for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, in Step 1. Thetitle compound was isolated as a white solid, 47 mg, 59.5%.

LC/MS: RT=1.81 Min (270 nm), m/z=464 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.21 (m, 1H), 1.46 (m, 1H), 1.66-2.13 (m, 4H), 2.86(m, 2H), 3.03 (t, 2H), 3.21 (d, 1H), 3.86 (s, 3H), 5.44 (s, 2H),7.07-7.19 (m, 3H), 7.42 (m, 1H), 7.70 (s, 1H), 8.04 (s, 1H), 8.06 (s,1H), 8.60 (s, 1H), 9.73 (br s, 1H), 11.22 (br s, 1H)

Example 92 1-(2-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 7, using the methodology described for Example 89, substituting1-(2-chloro-benzyl)-1H-pyrazole-4-carboxylic acid (86.5 mg, 0.365 mmol)for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, in Step 1. Thetitle compound was isolated as a white solid, 55 mg, 53.6%.

LC/MS: RT=1.86 Min (270 nm), m/z=480 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.17 (m, 1H), 1.44-1.72 (m, 5H), 2.84 (m, 2H), 3.04(t, 2H), 3.20 (d, 1H), 3.86 (s, 3H), 5.52 (s, 2H), 7.15 (m, 1H), 7.38(m, 2H), 7.52 (m, 1H), 7.73 (s, 1H), 8.04 (s, 1H), 8.06 (s, 1H), 8.50(s, 1H), 9.75 (br s, 1H), 11.22 (br s, 1H)

Example 93 1-(2-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 7, using the methodology described for Example 89, substituting1-(2-methyl-benzyl)-1H-pyrazole-4-carboxylic acid (79 mg, 0.365 mmol)for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, in Step 1. Thetitle compound was isolated as a white solid, 52 mg, 54.1%.

LC/MS: RT=1.86 Min (270 nm), m/z=460 [M+H]. Total run time 3.75 min(short pos), HP1100.

¹H NMR (d₆ DMSO): δ 1.17 (m, 1H), 1.42-1.74 (m, 5H), 2.28 (s, 3H), 2.83(m, 2H), 3.02 (t, 2H), 3.21 (d, 1H), 3.85 (s, 3H), 5.42 (s, 2H), 7.07(d, 1H), 7.24 (m, 3H), 7.72 (s, 1H), 8.01 (s, 1H), 8.06 (s, 1H), 8.41(s, 1H), 9.71 (br s, 1H), 11.21 (br s, 1H)

Example 94 1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the route outlined inScheme 8.

Step 1: Preparation of4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared as described in Example 6, Step 1,substituting 4-chloro-1H-pyrrolo[2,3-b]pyridine (5 g, 32.8 mmol) for4-bromo-1H-pyrrolo[2,3-b]pyridine. It was isolated as a colourless oil,8.27 g, 81.7%.

Step 2: Preparation of 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine

sec-Butyllithium solution, 1.4M in cyclohexane (15.82 mL, 22.15 mmol)was added drop wise to a solution of4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (3.91 g, 12.77mmol) in THF (50 mL) at −78° C. The reaction was stirred at −78° C. for30 minutes and then a solution of iodine (8.03 g, 31.64 mmol) in THF (25mL) was added drop wise and the reaction was stirred at −78° C. for afurther 45 minutes. The reaction was quenched by the addition ofsaturated aqueous ammonium chloride (50 mL) and the reaction allowed toattain RT. The mixture was extracted with iso-hexane (2×75 mL) and thecombined extracts washed with saturated aqueous sodium sulfite (×2) andsaturated aqueous sodium chloride. The solution was dried over anhydrousMgSO4 and concentrated to a colourless oil. This was taken up in THF (25mL) and tetrabutylammonium fluoride solution, 1.0M in THF (12.7 mL, 12.7mmol) was added drop wise at RT. The reaction mixture was stirred at RTfor 30 minutes and then partitioned between H₂O and EtOAc. The organiclayer was separated and the aqueous was extracted with more EtOAc. Thecombined organic phases were washed with saturated aqueous sodiumchloride, dried (MgSO₄) and concentrated in vacuo. The residue wasstirred in DCM, filtered and washed with DCM prior to drying in vacuo.This afforded the title compound as a white solid, 2.72 g, 77.3%.

Step 3: Preparation of1-benzenesulfonyl-4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine

Sodium hydride, 60% dispersion in mineral oil (0.508 g, 12.7 mmol) wasadded in portions to 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (2.72 g,10.74 mmol) in DMF (20 mL) at 0° C. The reaction was stirred for afurther 15 minutes and then benzene sulphonyl chloride (1.9 g, 1.37 mL,10.74 mmol) was added and the reaction stirred at RT for 2 hours. Thereaction mixture was diluted with H₂O and after stirring for 15 minutesthe precipitate was filtered off, washed with H₂O and with Et₂O. Thisfurnished the title compound as a white powder, 3.47 g, 84.8%, afterdrying in vacuo.

Step 4: Preparation of1-benzenesulfonyl-4-chloro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine

Copper (I) iodide (0.78 g, 4.1 mmol) was added to a solution of1-benzenesulfonyl-4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (1.43 g,3.42 mmol) in DMF (10 mL). The mixture was degassed and methyl2,2-difluoro-2-(fluorosulfonyl)acetate (2.3 g, 11.96 mmol) was added andmixture degassed again before heating at 100° C. for 2.5 hours. Thereaction was cooled to RT and diluted with EtOAc (40 mL). Theprecipitate was separated by filtering through a plug of celite. Thefiltrate was washed with H₂O (20 mL), saturated aqueous sodium chloride(20 mL), dried (MgSO₄) and concentrated in vacuo. The crude material waspurified by automated column chromatography eluting with iso-hexane to25% EtOAc/iso-hexane (gradient). Fractions containing pure product werecombined and concentrated in vacuo to afford the title compound as awhite solid, 0.46 g, 37.5%. Fractions containing pure product and smallimpurities were combined and concentrated in vacuo. The residue wastriturated with Et₂O to afford the title compound as a white powder,0.26 g, 21.3%. This gave a yield of 0.72 g, 58.8% overall.

Step 5: Preparation of4-chloro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine

1-benzenesulfonyl-4-chloro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine(1.5 g, 4.16 mmol) was stirred in THF (10 mL) and LiOH monohydrate (520mgs, 12.47 mmol) in H₂O (6 mL) was added. The reaction mixture wasstirred at RT for 64 hours and then the pH was adjusted to 7 by theaddition of saturated aqueous potassium hydrogen sulphate. This wasextracted with EtOAc (2×30 mL) and the combined organics washed withsaturated aqueous sodium chloride, dried over MgSO₄ and concentrated invacuo to afford the title compound as a pale yellow powder, 0.84 g,91.8%.

Step 6: Preparation of4-chloro-3-nitro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared according to the methodology describedfor Example 6, Step 5, substituting4-chloro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (842 mg, 3.82 mmol)for 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine. It was isolated as apale yellow powder, 0.78 g, 76.9%.

Step 7: Preparation of[(R)-1-(3-nitro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester

The title compound was prepared according to the methodology describedfor Example 89, Step 1, substituting4-chloro-3-nitro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (200 mg,0.75 mmol) for 4-fluoro-5-methoxy-3-nitro-1H-pyrrolo[2,3-b]pyridine. Itwas isolated as a yellow glass, 179 mg, 55.4%.

Step 8: Preparation of[(R)-1-(3-amino-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester

The title compound was prepared according to the methodology describedfor

Example 31, Step 8, substituting[(R)-1-(3-nitro-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester (179 mg, 0.42 mmol) for 2,2-dimethyl-propionicacid4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-3-nitro-1H-pyrrolo[2,3-b]pyridin-5-ylester. It was isolated as a green gum, 149 mgs, 88.9%.

Step 9: Preparation of[(R)-1-(3-{[1-(4-Fluoro-benzyl)-1H-pyrazole-4-carbonyl]-amino}-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester

1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid (synthesis describedin Example 17) was stirred as a suspension in DCM (2 mL) and oxalylchloride, 2.0M solution in DCM (0.17 mL, 0.34 mmol) was added drop wiseat RT followed by a drop of DMF. The reaction was stirred for a further15 minutes and the subsequent solution was concentrated in vacuo. Theresidue was taken up in DCM (1 mL) and added drop wise to a solution of[(R)-1-(3-amino-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester (62.3 mg, 0.28 mmol) in DCM (2 mL) containing Et₃N(90 mg, 0.12 mL, 0.85 mmol). After stirring for a further 1 hour thereaction was diluted with DCM and washed with H₂O. The organics wereseparated, dried (MgSO₄) and concentrated in vacuo. The residue wastaken up in MeOH (5 mL) and after 50% w/v NaOH (1 mL) was added, themixture was stirred for 18 hours at RT. The solvent removed in vacuo andthe residue taken up in DCM. It was washed with H₂O, saturated aqueoussodium chloride, dried over MgSO₄ and concentrated in vacuo. The crudematerial was purified via automated column chromatography eluting with25% EtOAc/iso-hexane to EtOAc (gradient). The fractions containingproduct were combined and concentrated in vacuo to afford the titlecompound as a yellow glass, 52 mg, 30.6%.

Step 10: Preparation of title compound:1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

[(R)-1-(3-{[1-(4-Fluoro-benzyl)-1H-pyrazole-4-carbonyl]-amino}-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester (50 mg, 0.08 mmol) was taken up in hydrochloricacid solution, 1.25M in MeOH (2 mL) and heated under microwaveirradiation at 80° C. for 30 minutes. The solvent was removed in vacuoand residue taken up in minimum volume of MeOH and applied to a SCX-2ion exchange cartridge. This was washed with MeOH and desired compoundeluted with 4:1 DCM/7N NH₃ in MeOH and concentrated in vacuo. The crudematerial was further purified via automated column chromatographyeluting with DCM to 15% MeOH (containing 5% 7N NH₃ in MeOH)/DCM(gradient). The fractions found to contain product were combined andconcentrated in vacuo. The residue was triturated with diethyl ether toafford the title compound as a cream powder, 4.5 mgs, 10.8%.

LC/MS: RT=0.93 Min (230 nm), m/z=502.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 0.82-0.93 (m, 1H), 1.38-1.50 (m, 1H), 1.54-1.65 (m,2H), 2.70-2.81 (m, 2H), 2.80-3.00 (m, 2H), 3.1-3.09 (m, 1H), 5.42 (s,2H), 7.16-7.24 (m, 2H), 7.28-7.36 (m, 2H), 7.70 (s, 1H), 8.08 (s, 1H),8.45-8.48 (m, 2H), 9.62 (br s, 1H), 11.60-12.60 (br s, 1H) 2 protons notseen

Example 95 1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the methodology describedfor Example 94 in Steps 1 to 8.

Step 9: Preparation of((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester

This was prepared using the methodology described for Example 31, Step9, substituting[(R)-1-(3-amino-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester (60 mg, 0.15 mmol) for 2,2-dimethyl-propionic acid3-amino-4-((R)-3-tert-butoxycarbonylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylester and DIPEA (40 mg, 50 uL, 0.3 mmol) for Et₃N. The title compoundwas isolated as a dark yellow glass, 63 mg, 71.9%.

Step 10: preparation of title compound:1-benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

This was prepared using the methodology described for Example 94, Step10, substituting((R)-1-{3-[(1-benzyl-1H-pyrazole-4-carbonyl)-amino]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl}-piperidin-3-yl)-carbamicacid tert-butyl ester (63 mg, 0.11 mmol) for[(R)-1-(3-{[1-(4-fluoro-benzyl)-1H-pyrazole-4-carbonyl]-amino}-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl]-carbamicacid tert-butyl ester. After the usual work up, the residue was taken upin minimum volume of MeOH and applied to a SCX-2 ion exchange cartridge.

This was washed with MeOH and the desired compound eluted with 4:1DCM/7N NH₃ in MeOH and concentrated in vacuo. The material was furtherpurified by trituration with Et₂O and then MeCN. This afforded the titlecompound as a beige powder, 4.3 mg, 8.2%.

LC/MS: RT=0.91 Min (230 nm), m/z=484.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 0.90-1.00 (m, 1H), 1.40-1.51 (m, 1H), 1.54-1.68 (m,2H), 2.80-3.00 (m, 4H), 3.07-3.13 (m, 1H), 5.42 (s, 2H), 7.20-7.40 (m,5H), 7.70 (s, 1H), 8.10 (s, 1H), 8.45-8.50 (m, 2H), 9.65 (br s, 1H),11.00-13.00 (br s, 1H) 2 protons not seen

Example 96 1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the methodology describedfor Example 94, substituting1-pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid (57.5 mg, 0.28 mmol)for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, in Step 9. Thetitle compound was isolated as a beige powder, 11.7 mg, 28.2%.

LC/MS: RT=0.78 Min (230 nm), m/z=485 [M+H]. Total run time 1.9 min(super short pos), H P1200.

¹H NMR (d₆ DMSO): δ 0.83-0.93 (m, 1H), 1.38-1.51 (m, 1H), 1.54-1.64 (m,2H), 2.71-2.82 (m, 2H), 2.84-3.00 (m, 2H), 3.02-3.10 (m, 1H), 5.48 (s,2H), 7.38-7.43 (m, 1H), 7.63-7.72 (m, 2H), 8.10, (s, 1H), 8.45 (s, 1H),8.50-8.55 (m, 3H), 9.65 (br s, 1H), 11.60-12.60 (br s, 1H) 2 protons notseen

Example 97 1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide

The title compound was prepared according to the methodology describedfor Example 94, substituting1-pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid (57.5 mg, 0.28 mmol)for 1-(4-fluoro-benzyl)-1H-pyrazole-4-carboxylic acid, in Step 9. Thetitle compound was isolated as a beige powder, 15.1 mg, 43.4%.

LC/MS: RT=0.82 Min (230 nm), m/z=485.2 [M+H]. Total run time 1.9 min(super short pos), HP1200.

¹H NMR (d₆ DMSO): δ 0.88-0.99 (m, 1H), 1.42-1.54 (m, 1H), 1.57-1.69 (m,2H), 2.73-2.84 (m, 2H), 2.84-3.00 (m, 2H), 3.04-3.11 (m, 1H), 5.53 (s,2H), 7.10 (d, 1H), 7.31-7.37 (m, 1H), 7.72 (s, 1H), 7.80 (m, 1H), 8.07,(s, 1H), 8.45-8.57 (m, 3H), 9.68 (br s, 1H), 11.60-12.60 (br s, 1H) 2protons not seen

General Procedures

All reagents obtained from commercial sources were used without furtherpurification. Anhydrous solvents were obtained from commercial sourcesand used without further drying. Flash chromatography was performed withpre-packed silica-gel cartridges (Isolute Flash Si II, 56 Å, Biotage).Automated flash chromatography was performed on a Teledyne IscoCombiFlash® Rf purification system with pre-packed silica-gel cartridges(SilaSep™ Flash, 60 Å, Silicycle). Ion exchange chromatography wasperformed using isolute SCX-2, SPE columns, Biotage. Thin layerchromatography was conducted with 5×10 cm plates coated with Silica 60(Machery-Nagel). Microwave heating was performed with a BiotageInitiator Eight™ 2.0 instrument, a CEM explorer 24 or a CEM explorer 48.

The compounds of the present invention were characterized by highperformance liquid chromatography-mass spectroscopy (HPLC-MS) on eitheran Agilent HP1200 Rapid Resolution Mass detector 6140 multimode sourceM/z range 150 to 1000 amu or an Agilent HP1100 Mass detector 1946D ESIsource M/z range 150 to 1000 amu. The conditions and methods listedbelow are identical for both machines.

Column for 7.5 min run: GeminiNX, 5 μm, C18, 30×2.1 mm (Phenomenex) orZorbax Eclipse Plus, 3.5 μm, C18, 30×2.1 mm (Agilent).

Temperature: 35° C.

Column for 3.75 min run: GeminiNX, 5 μm, C18, 30×2.1 mm (Phenomenex) orZorbax Eclipse Plus, 3.5 μm, C18, 30×2.1 mm (Agilent).

Temperature: 35° C.

Column for 1.9 min run: Kinetex, 2.5 μm, C18, 50×2.1 mm (Phenomenex) orAccucore, 2.6 μm, C18, 50×2.1 mm.

Temperature: 55° C.

Mobile Phase: A—H₂O+10 mmol/ammonium formate+0.08% (v/v) formic acid atpH ca 3.5.

B—95% Acetonitrile+5% A+0.08% (v/v) formic acid.

Injection Volume: 1 μL

“Short” method gradient table, either positive (pos) or positive andnegative (pos/neg) ionisation

Time (min) Solvent A (%) Solvent B (%) Flow (mL/min) 0 95 5 1 0.25 95 51 2.50 5 95 1 2.55 5 95 1.7 3.60 5 95 1.7 3.65 5 95 1 3.70 95 5 1 3.7595 5 1

“Super Short” method gradient table, either positive (pos) or positiveand negative (pos/neg) ionisation

Flow Time (min) Solvent A (%) Solvent B (%) (mL/min) 0 95 5 1.3 0.12 955 1.3 1.30 5 95 1.3 1.35 5 95 1.6 1.85 5 95 1.6 1.90 5 95 1.3 1.95 95 51.3

“Long” method gradient table, either positive (pos) or positive andnegative (pos/neg) ionisation

Time (min) Solvent A (%) Solvent B (%) Flow (mL/min) 0 95 5 1 0.25 95 51 5.50 5 95 1 7.25 5 95 1 7.50 95 5 1

Detection: UV detection at 230, 254 and 270 nm.

The compounds of the present invention were also characterized byNuclear Magnetic Resonance (NMR). Analysis was performed with a BrukerDPX400 spectrometer and proton NMR spectra were measured at 400 MHz. Thespectral reference was the known chemical shift of the solvent. ProtonNMR data is reported as follows: chemical shift (b) in ppm, followed bythe multiplicity, where s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, dd=doublet of doublets, dt=doublet of triplets, dm=doubletof multiplets, ddd=doublet of double doublets, td=triplet of doublets,qd=quartet of doublets and br=broad, and finally the integration.

Some compounds of the invention were purified by preparative HPLC. Thesewere performed on a H₂Os FractionLynx MS autopurification system, with aGemini-NX® 5 μm, C18, 100 mm×21 mm i.d. Axia column from Phenomenex,running at a flow rate of 20 cm³ min⁻¹ with UV diode array detection(210 and mass-directed collection. Gradients used for each compound areshown in Tables above.

At pH 4:

solvent A=10 mM ammonium formate in HPLC grade H₂O+0.08% v/v formicacid. Solvent B=95% v/v HPLC grade acetonitrile+5% v/v solvent A+0.08%v/v formic acid. At pH 9:

solvent A=10 mM ammonium formate in HPLC grade H₂O+0.08% v/v ammoniasolution. Solvent B=95% v/v HPLC grade MeOH+5% v/v solvent A+0.08% v/vammonia solution.

The mass spectrometer was a H₂Os Micromass ZQ2000 spectrometer,operating in positive and negative ion electrospray ionisation modes,with a molecular weight scan range of 150 to 1000.

IUPAC chemical names were generated using AutoNom Standard.

Assay Protocols CHK1 Enzyme Assay

Assays for the CHK1 kinase activity were carried out by monitoring thephosphorylation of a synthetic peptide Chktide with the amino acidsequence, KKKVSRSGLYRSPSMPENLNRPR. The assay mixture containing theinhibitor and CHK1 enzyme was mixed together in a microtiter plate in afinal volume of 50 μl and incubated for 40 minutes at 30° C.

The assay mixture contained 0.02 mM unlabeled ATP, 0.5 μCi ³³P-γ-ATP, 15μM Chktide, 0.1 mg/mL BSA, 50 mM Hepes-NaOH pH 7.5 and 5 nMCHK-1(1-289)-8HIS (Vernalis) enzyme. The reaction was stopped by adding504 of 50 mM phosphoric acid. 90 μL of the mixture was transferred to apre-wetted 96-well multi-screen MAPHNOB filtration plate (Millipore) andfiltered on a vacuum manifold. The filter plate was washed with 3successive additions of 100 μl 50 mM phosphoric acid and then with 504MeOH. The filtration plate was dried for 10 min at 65° C., scintillantadded and phosphorylated peptide quantified in a scintillation counter(Trilux, PerkinElmer).

CHK-1 Enzyme Assay (TR-FRET)

CHK activity was also assessed using LanthaScreen TR-FRET technology(Life Technologies) by monitoring the phosphorylation of a syntheticfluorescein-labelled peptide based on ezrin/radixin/moesin (ERM) (aminoacid sequence GAGRLGRDKYKTLRQIRQ). The assay mixture containing theinhibitor and CHK-1 enzyme was mixed together in a microtiter plate in afinal volume of 20 μl and incubated for 80 minutes at 30° C.

The assay mixture contained 50 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM EGTA,0.01% Brij-35, 200 μM ATP, 400 nM fluorescein-labelled ERM (LifeTechnologies), and 1 nM full length HIS-tagged CHK-1 (LifeTechnologies). The reaction was stopped by adding 204 of TR-FRETdilution buffer (Life Technologies) containing 20 mM EDTA and 1 nMterbium-labelled anti-pERM antibody (Life Technologies). The quenchedreaction was incubated for 30 minutes at room temperature with shakingto allow antibody to bind to phosphorylated ERM, and then fluorescencefrom the donor fluorophore (terbium) and acceptor fluorophore(fluorescein) was measured using a Synergy2 Multi-Mode Microplate Reader(BioTek) at 495 nm and 520 nm respectively. The TR-FRET ratio wascalculated as 520 nm/495 nm.

CHK-1 Binding Assay (TR-FRET)

Compounds were assessed for CHK-1 binding using LanthaScreen TR-FRETtechnology (Life Technology). Assay mixture containing inhibitor, 50 mMHEPES pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.01% Brij-35, 2 nMbiotin-labelled anti-HIS tag antibody (Life Technologies), 2 nMEuropium-labelled streptavidin (Life Technologies), 100 nMAlexaFluor-labelled Tracer236 (Life Technologies), and either 10 nM or30 nM CHK-1(1-289)-8HIS (Vernalis) enzyme, was incubated in a microtitreplate for 120 minutes at 23° C. A final volume of 15 μL was used.

Fluorescence from the donor fluorophore (europium) and acceptorfluorophore (Alexa Fluor) was measured using a Synergy2 Multi-ModeMicroplate Reader (BioTek) at 620 nm and 665 nm respectively. TheTR-FRET ratio was calculated as 665 nm/620 nm.

All the compounds exemplified in the patent were tested in one, two orall three of the above assays and were found to have an IC₅₀ of lessthan 1 μM. A majority of Examples 1-97 were found to have an IC₅₀ ofless than 0.1 μM.

CHK1 Cellular Assay—Gemcitabine EC₅₀ Assay

HT29 cells were purchased from ATCC (Manassas, Va., US) and cultured inDulbecco's modified Eagles medium (DMEM) supplemented with 10% foetalcalf serum (FCS) and penicillin/streptomycin at 37° C., 5% CO₂ in ahumidified incubator. 5×10³ HT29 cells were seeded per well of a 96-wellplate and allowed to incubate overnight. Tripling dilutions of compound,prepared in DMEM/10% FCS plus 15 nM gemcitabine, were added to the cellsand incubated at 37° C. for 72 hours. Cells were then fixed with 10%trichloroacetic acid (TCA) stained with sulphorhodamine B (SRB) and theabsorbance determined at 540 nm. Curves were analysed using XLFit 4(Excel) with model 205 (fit=(A+((B−A)/(1+((C/x)̂D))))). The EC₅₀ wasdetermined as the concentration of compound that inhibited growth by 50%at a given concentration of gemcitabine.

All the compounds exemplified in the patent were tested in the aboveassay in the presence of gemcitabine at 15 nM, and were found to have anEC₅₀ of less than 1 μM. A majority of Examples 1-97 were found to havean EC₅₀ of less than 0.1 μM.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Z isindependently (Alk)_(n)-R_(n)-(Alk)_(n)-X, wherein each Alk isindependently (C₁ to C₁₂) alkylene or (C₂ to C₁₂) alkenylene, each ofwhich may be optionally substituted; each n is independently 0 or 1;each R is independently optionally substituted arylene or heteroarylene,or optionally substituted cycloalkylene or heterocyclic, —O—, —S—,—(C═O)—, —(C═S)—, —SO₂—, —C(═O)O—, —C(═O)NR^(A)—, —C(═S)NR^(A)—,—SO₂NR^(A)—, —NR^(A)C(═O)—, —NR^(A)SO₂— or NR^(A)— wherein R^(A) ishydrogen, C₁-C₆ alkyl, —C₁-C₆ alkyl(cycloalkyl), C₁-C₆ alkyl(C₁-C₆alkoxy) or C₁-C₆ alkoxy; each X is independently halogen, —H, —OR^(A),NR^(A)R^(A), optionally substituted aryl or heteroaryl, or optionallysubstituted cycloalkyl or heterocyclic, CN or C(halogen)_(a)H_(b), wherea is 1, 2, or 3, and b is (3-a); Y is optionally substituted aryl orheteroaryl, or optionally substituted cycloalkyl or heterocyclic; and R¹is H or C₁-C₆ alkyl, with the proviso that the compound is notN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamideor (R)-tert-butyl1-(5-bromo-3-(1-(4-methoxybenzyl)-1Hpyrazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate.2. The compound according to claim 1, wherein Y is not phenylsubstituted with O-methyl.
 3. The compound according to claim 1, whereinR^(A) is hydrogen or C₁-C₆ alkyl.
 4. The compound according to claim 1,wherein at least one Z is H, halogen, optionally substituted aryl,optionally substituted heteroaryl, optionally substitutednitrogen-containing heterocycle, C₁ to C₆ alkyl or OR^(A).
 5. Thecompound according to claim 4, wherein one Z group is H, halogen, OR^(A)or C₁ to C₆ alkyl, and the other Z group is optionally substituted arylor optionally substituted nitrogen-containing heterocycle.
 6. Thecompound according to claim 5, wherein the nitrogen-containingheterocycle is substituted with NR^(A)R^(A).
 7. The compound accordingto claim 1, wherein at least one Z is (Alk)_(n)-optionally substitutedarylene-(Alk)_(n)-optionally substituted heterocycle.
 8. The compoundaccording to claim 1, wherein R¹ is H.
 9. The compound according toclaim 1, wherein C₁ to C₆ alkyl includes a cycloalkyl portion.
 10. Thecompound according to claim 1, wherein Y is phenyl or heteroaryloptionally substituted with C₁ to C₆ alkyl, OR^(A), halogen or C₁ to C₆alkoxy.
 11. The compound according to claim 10, wherein Y is pyridyl,pyrrolyl, phenyl, or phenyl substituted with methyl, bromine orchlorine.
 12. The compound according to claim 1, which has the formulaIa:

or a pharmaceutically acceptable salt thereof, wherein: Z₁ and Z₂ areindependently (Alk)_(n)-R_(n)-(Alk)_(n)-X.
 13. The compound according toclaim 12, wherein Z₁ is halogen, phenyl, OR^(A) or C₁ to C₆ alkyl, andZ₂ is optionally substituted aryl or optionally substituted heterocycle.14. The compound according to claim 12, wherein Z₂ is halogen, CF₃,cyclopropyl, phenyl, OR^(A) or C₁ to C₆ alkyl, and Z₁ is optionallysubstituted aryl or optionally substituted heterocycle.
 15. The compoundaccording to claim 12, wherein the heterocycle or nitrogen-containingheterocycle is an optionally substituted piperidine, piperazine ormorpholine.
 16. A compound listed below, or a pharmaceuticallyacceptable salt thereof: 1-Benzyl-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide;1-Benzyl-1H-pyrazole-4-carboxylic acid(1H-pyrrolo[2,3-b]pyridin-3-yl)-amide; 1-Benzyl-1H-pyrazole-4-carboxylicacid (4-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide;1-Benzyl-1H-pyrazole-4-carboxylic acid(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide; or1-Benzyl-1H-pyrazole-4-carboxylic acid(5-piperidin-1-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide;N-{4-[(3R)-3-Aminopiperidin-1-yl]-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl}-1-benzyl-1H-pyrazole-4-carboxamide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-methylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-ethylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-hydroxy-pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-hydroxy-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-(3-dimethylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-bromo-4-[(R)-3-(cyclopentylmethyl-amino)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-bromo-4-((R)-3-isobutylamino-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-bromo-4-[(R)-3-(2,2-dimethyl-propylamino)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-bromo-4-[(R)-3-(cyclopropylmethyl-amino)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Methoxy-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amideN-{4-[(3R)-3-aminopiperidin-1-yl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}-1-benzyl-1H-pyrazole-4-carboxamide1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Methoxy-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-pyrrolidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amideN-{4-[(3R)-3-aminopiperidin-1-yl]-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-1-benzyl-1H-pyrazole-4-carboxamide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-piperidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl]-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(4-fluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-dimethylaminomethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(3-fluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-methylaminomethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(4-morpholin-4-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(3,3-difluoro-pyrrolidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-dimethylaminomethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3-fluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3,3-difluoro-piperidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-azetidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3,3-difluoro-azetidin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(5-pyrrolidin-1-ylmethyl-thiophen-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[5-(3,3-difluoro-azetidin-1-ylmethyl)-thiophen-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3-dimethylamino-2,2-dimethyl-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(3-morpholin-4-yl-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(oxetan-3-yloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((3R,4R)-3-amino-4-cyclopropyl-piperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(2-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(3-pyrrolidin-1-yl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-Benzyl-1H-pyrazole-4-carboxylic acid(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-(3-Methoxy-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-(2-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-(2-Cyano-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-(1H-Pyrrol-2-ylmethyl)-1H-pyrazole-4-carboxyl ic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-Benzyl-1H-pyrazole-4-carboxylic acid(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-Benzyl-1H-pyrazole-4-carboxylic acid(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-(3-Methoxy-benzyl)-1H-pyrazole-4-carboxylic acid(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[3-(1-methyl-piperidin-3-yloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[4-(3-dimethylamino-propoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[1-(2-diethylamino-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Benzyl-1H-pyrazole-4-carboxylic acid{5-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-amide1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-4-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(3-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(3-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(2-Chloro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(2-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-(4-Fluoro-benzyl)-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Benzyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-3-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide1-Pyridin-2-ylmethyl-1H-pyrazole-4-carboxylic acid[4-((R)-3-amino-piperidin-1-yl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-amide17. A pharmaceutical composition comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Z isindependently (Alk)_(n)-R_(n)-(Alk)_(n)-X, wherein each Alk isindependently (C₁ to C₁₂) alkylene or (C₂ to C₁₂) alkenylene, each ofwhich may be optionally substituted; each n is independently 0 or 1;each R is independently optionally substituted arylene or heteroarylene,or optionally substituted cycloalkylene or heterocyclic, —O—, —S—,—(C═O)—, —(C═S)—, —SO₂—, —C(═O)O—, —C(═O)NR^(A)—, —C(═S)NR^(A)—,—SO₂NR^(A)—, —NR^(A)C(═O)—, —NR^(A)SO₂— or NR^(A)— wherein R^(A) ishydrogen, C₁-C₆ alkyl, —C₁-C₆ alkyl(cycloalkyl), C₁-C₆ alkyl(C₁-C₆alkoxy) or C₁-C₆ alkoxy; each X is independently halogen, —H, —OR^(A),NR^(A)R^(A), optionally substituted aryl or heteroaryl, or optionallysubstituted cycloalkyl or heterocyclic, CN or C(halogen)_(a)H_(b), wherea is 1, 2, or 3, and b is (3-a); Y is optionally substituted aryl orheteroaryl, or optionally substituted cycloalkyl or heterocyclic; and R¹is H or C₁-C₆ alkyl, and one or more pharmaceutically acceptablecarriers and/or excipients. 18-19. (canceled)
 20. A method for treatinga condition responsive to inhibition of protein kinase activitycomprising administering a therapeutically effective amount of acompound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: each Z isindependently (Alk)_(n)-R_(n)-(Alk)_(n)-X, wherein each Alk isindependently (C₁ to C₁₂) alkylene or (C₂ to C₁₂) alkenylene, each ofwhich may be optionally substituted; each n is independently 0 or 1;each R is independently optionally substituted arylene or heteroarylene,or optionally substituted cycloalkylene or heterocyclic, —O—, —S—,—(C═O)—, —(C═S)—, —SO₂—, —C(═O)O—, —C(═O)NR^(A)—, —C(═S)NR^(A)—,—NR^(A)C(═O)—, —NR^(A)SO₂— or NR^(A)— wherein R^(A) is hydrogen, C₁-C₆alkyl, —C₁-C₆ alkyl(cycloalkyl), C₁-C₆alkyl(C₁-C₆alkoxy) or C₁-C₆alkoxy;each X is independently halogen, —H, —OR^(A), NR^(A)R^(A), optionallysubstituted aryl or heteroaryl, or optionally substituted cycloalkyl orheterocyclic, CN or C(halogen)_(a)H_(b), where a is 1, 2, or 3, and b is(3-a); Y is optionally substituted aryl or heteroaryl, or optionallysubstituted cycloalkyl or heterocyclic; and R¹ is H or C₁-C₆ alkyl, 21.(canceled)
 22. The method according to claim 21, wherein the proteinkinase is CHK1.
 23. The method according to claim 21, wherein thecondition responsive to inhibition of protein kinase activity isselected from cancer and autoimmune disorders.
 24. The method accordingto claim 23, wherein said autoimmune disorder is organ transplantrejection, lupus, multiple sclerosis, rheumatoid arthritis orosteoarthritis. 25.-26. (canceled)
 27. The pharmaceutical compositionaccording to claim 17, wherein at least one Z is H, halogen, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted nitrogen-containing heterocycle, C₁ to C₆ alkyl or OR^(A).28. The pharmaceutical composition according to claim 17, wherein R¹ isH.
 29. The pharmaceutical composition according to claim 17, wherein Yis phenyl or heteroaryl optionally substituted with C₁ to C₆ alkyl,OR^(A), halogen or C₁ to C₆ alkoxy.